tbuckley/cabot-search huggingface dataset:
Implementation of systematic genetic counseling (GC) and multigene germline testing (MGT) for pancreatic cancer (PC) patients (pts).
Authors: Matthew B. Yurgelun, Anu B. Chittenden, Chinedu I. Ukaegbu, Kimberly Perez, Audrey P. Madigan, Shraddha Gaonkar, James M. Cleary, Andrew Aguirre, Brian M. Wolpin, Sapna Syngal
Journal: Journal of Clinical Oncology (2020)

678 Background: MGT identifies cancer susceptibility gene variants in 4-10% of unselected PC pts. Such data have prompted national guidelines to recommend GC and MGT of all PC pts, but the benefits and barriers to implementing systematic testing are unknown. This study’s aim was to study the implementation of universal GC for all PC pts seen in an academic oncology practice. Methods: In 12/2016, all Dana-Farber Cancer Institute (DFCI) gastrointestinal oncologists were recommended to refer all PC pts for GC and MGT. In 10/2018, workflows were changed such that PC patients were automatically scheduled for GC consultation on the same day as their initial oncologic evaluation (unless patients opted out), rather than relying on provider referral. Clinical and germline data were collected on a consecutive cohort of PC pts undergoing GC and MGT from 3/1/2017-3/31/2019. Two additional months (4/1/2019-5/31/2019) were collected for clinical quality assessment purposes. Results: 1305 (48.3/month) PC pts were seen for oncologic new patient visits, 318 (25.1%; 12.1/month) of whom underwent GC. Rates of GC/MGT increased significantly after the 10/2018 workflow change (8.2 PC pts/month [17.2% of all new PC pts seen] versus 20.3 PC pts/month, [40.9% of all new PC pts seen]; p&lt;0.01). Of the 318 PC pts who underwent GC, 29 (9.1%; 95% CI 6.4-11.9%; 2.2% of all PC pts seen) were found to carry germline PC susceptibility gene mutations on MGT. Rates of mutation carrier identification increased after the clinical workflow change from 0.79 mutation carriers/month (1.6% of all new PC pts seen) to 1.75 mutation carriers/month (3.5% of all new PC pts seen). The majority of identified mutation carriers have either received therapy targeted towards their germline mutation or are undergoing first-line palliative systemic therapy with potential for future targeted therapy. Conclusions: Clinical implementation of routine GC/MGT in PC pts is feasible and results in the detection of mutations that are actionable for PC pts and at-risk family members. Systematized workflows for GC evaluation not reliant on active referral result in markedly higher uptake of MGT and mutation carrier identification. Clinical trial information: NCT03060720.
Relationship of lymphopenia to overall survival and progression-free survival in rectal cancer patients receiving neoadjuvant chemoradiation.
Authors: Jackson Neal Howell, Bailey Nelson, David Cady, Jordan Kharofa
Journal: Journal of Clinical Oncology (2020)

39 Background: Pelvic radiation and myelosuppressive chemotherapy can lead to lymphopenia during the course of preoperative chemoradiation when treating rectal cancer. Lymphopenia during chemoradiation has been associated with higher risks of recurrence in other cancers, possibly due to decreased immunosurveillance. The effect in rectal cancer is not well described. We hypothesize that high-grade lymphopenia is associated with worse progression-free survival (PFS) and overall survival (OS) in rectal cancer patients undergoing preoperative chemoradiation. Methods: All patients treated at our institution with neoadjuvant chemoradiation between 2013 and 2019 were reviewed (n = 99). The study was limited to patients with Stage II – IV (AJCC 8th edition) rectal adenocarcinoma. Patients were excluded if they had prior systemic therapy (n = 13) or if lymphocyte data was unavailable (n = 30). Lymphopenia which arose during or within 30 days of completion of chemoradiation was graded by the CTCAE v.4.0. Neoadjuvant Rectal (NAR) scores, indicators of pathologic response, were calculated for each surgical patient. Kaplan-Meier analysis was used to calculate PFS and OS. Two-tailed t-tests (a=0.05) were used to detect differences between subgroups. Results: Fifty-six patients met inclusion criteria. Grade 2 (G2) or higher lymphopenia occurred in 43 (76.8%) patients (G2 = 22, G3 = 20, G4 = 1). In patients with G2 vs G3-4 lymphopenia, there were no differences in baseline, treatment, or demographic characteristics. The median PFS for these patients was 20.0 months. Patients with G3-4 lymphopenia had significantly worse 2-year PFS compared to those with G2 lymphopenia (83.3% vs 59.3% p = 0.03). The two-year OS did not differ between groups (100% vs 60.3%, p = 0.10). Lymphocyte nadir did not correlate with pathologic response, as measured by the NAR score (r = -0.28, p = 0.07). Conclusions: In this study, G3-4 lymphopenia was associated with worse PFS in rectal cancer patients treated with neoadjuvant chemoradiation, despite a small sample size. The prognostic implications of lymphopenia in rectal cancer should be confirmed in larger cohorts and the underlying mechanisms explored.
Role of para-aortic lymph node sampling in pancreatic cancer surgery.
Authors: Yusuke Kazami, Hiromichi Ito, Yoshihiro Ono, Takafumi Sato, Yosuke Inoue, Yu Takahashi
Journal: Journal of Clinical Oncology (2020)

715 Background: In the management of pancreatic cancer, para-aortic lymph node (PALN) metastasis is regarded as distant metastasis, and systemic treatment is recommended. However, imaging study is not perfect to detect all PALN metastasis and the management of intraoperatively discovered PALN has been controversial. We hypothesized that sampling of PALNs on exploration could allow us to avoid pancreatic resection for patients who would not benefit. In this study, we evaluated the incidence and the effect on the long-term outcomes for patients with potentially resectable pancreatic cancer. Methods: Three hundred and ninety-two patients who had PALNs sampled upon potentially resectable pancreatic cancer from 2005 through 2014 were included in the study. All patients were appropriately staged preoperatively with CT/MRI and those with suspected PALN metastasis were not considered as candidates for resection. The patients whose resections were aborted because of liver metastasis or peritoneal dissemination discovered on exploration, or those who died within 30-days after the operation were not included. Evaluated outcomes were incidence of PALN metastasis and their recurrence-free and overall survivals (RFS, OS). Results: The patients’ median age was 74 years, and 58.6% was man. 67.8% had tumors at pancreatic head. Preoperative chemotherapy was given only on 16 patients (3.2%). Among 392 patients with PALNs sampled, 53 (13.5%) patients had metastasis; Resection was completed on 40 patients and resection was aborted on the rest. Among patients who underwent pancreatic resection, median RFS and OS were 10 and 12 months for patients with PALN metastasis, compared to 17 and 26 months for those without PALN metastasis (p &lt; 0.001 for RFS and p &lt; 0.001 for OS). The 5-year-OS rates for patients with/without PALN metastasis were 5.9% and 25% (p &lt; 0.001). Among 53 patients with PALN metastasis, OS were not different between the patients who underwent resection and those who did not (median 13 months vs 17 months, p = 0.06), and there were no recurrence-free survivors. Conclusions: PALN sampling and evaluation before committing to resection is useful to identify the patients who can unlikely benefit and to avoid unnecessary morbid operation.
Using Real-world Historical Controls to Evaluate Radiation Dose Escalation in Esophageal Cancer
Authors: Liyuan Fan, Baosheng Li, Chen Hu
Journal: JAMA Oncology (2020)

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PD-L1 profiling of circulating tumor cells for immune checkpoint inhibitor therapy in head and neck cancers.
Authors: Revati Patil, Dadasaheb B. Akolkar, Darshana Patil, Pradip Devhare, Navin Srivastava, Pooja Fulmali, Shoeb Patel, Pradyumna Shejwalkar, Vineet Datta, Cynthe Sims, Ajay Srinivasan, Rajan Datar
Journal: Journal of Clinical Oncology (2020)

36 Background: Selection of Immune Checkpoint Inhibitor (ICI) therapies in Head and Neck cancers are based on IHC based detection of PD-L1 expression in tumor tissue. Invasive biopsy to obtain tumor tissue for IHC is associated with procedural risks, sequelae and expenses. Prior efforts at PD-L1 profiling of Circulating Tumor Cells (CTCs) have been constrained by low CTC yields. We employed a novel approach for harvesting sufficient CTCs from Head and Neck cancers that permit PD-L1 profiling by Immunocytochemistry (ICC). Methods: 15 ml peripheral blood was collected from 95 patients with head and neck squamous cell carcinomas (HNSCC). CTCs were enriched from PBMCs via an epigenetically acting stabilization process which induced apoptosis in non-malignant cells and conferred survival privilege on apoptosis-resistant CTCs, which were harvested and confirmed by immunostaining for EpCAM and pan-CK. Deep ICC profiling of CTCs was performed with organ-specific markers as well as PD-L1:22c3 and PD-L1:28-8 clones. Results: Viable CTCs could be enriched and harvested in 90 out of 95 samples (95.3%) regardless of metastatic or treatment status. Deep ICC and PD-L1 profiling could be performed in all 90 samples (100%). PD-L1 expression was quantitatively assigned as ‘Low’, ‘Moderate’ or ‘High’. 28 (31.1%) samples were positive for PD-L1:28-8 (27 Low + 1 Moderate) and 26 (28.9%) samples were positive for PD-L1:22c3 (24 Low + 2 Moderate). 15 samples were positive for both PD-L1 clones. Conclusions: CTCs in Head and Neck squamous cell carcinomas can be considered for evaluating PD-L1 expression in patients where ICI therapies are otherwise viable.
Tumor downsizing following neoadjuvant therapy for borderline-resectable pancreatic adenocarcinoma.
Authors: Joseph Arturo Reza, Alberto Monreal, Patrick Hunter Meyer, Swati Patel, Ahmed Zakari, Sebastian de la Fuente
Journal: Journal of Clinical Oncology (2020)

690 Background: Downstaging of pancreatic adenocarcinoma in patients presenting with nonmetastatic, unresectable disease has proven to be associated with improved clinical outcomes. Efforts at rescuing these patients to become surgical candidates are commonly attempted with a combination of systemic and radiation strategies. In this study, we aimed to determine tumor downsizing in patients that underwent neoadjuvant systemic therapy followed by a curative-intended surgical resection. Methods: A retrospective review of consecutive patients that underwent surgical resection for pancreatic adenocarcinoma following a course of neoadjuvant therapy was performed. Basic demographics, endoscopic ultrasound (EUS) findings, chemotherapy regimens and duration, rates of radiotherapy, type of surgical procedure and pathologic results were recorded. Tumor response to neoadjuvant therapy was established by correlating EUS- to pathologic tumor dimensions. Analysis of the data was done using Mann-Whitney U test, Pearson correlation and Chi-square when indicated. Results: A total of 97 patients were analyzed; 40 underwent neoadjuvant chemotherapy (13 patients also received concurrent radiation therapy). In those 57 patients that were resected upfront, EUS tended to underestimate tumor sizes significantly compared to pathologic dimensions, with an average difference between dimensions of 0.66 cm (p = 0.0004). Within the group treated with neoadjuvant chemotherapy, 90% of patients had downsizing at an average of 8% of tumor size. There were no differences in rates of tumor downsizing between FOLFIRINOX or Gemcitabine/Nac-paclitaxel treated patients. In addition, there were no correlations in margin status (R0) based on chemotherapy used, with both regimens achieving a similar rate of R0 resections (mean 61%). The type of chemotherapy regimen used did not affect the ratio of positive lymph nodes harvested. Conclusions: In patients that present with borderline resectable pancreatic adenocarcinoma, a course of neoadjuvant therapy results in tumor downsizing in a significant number allowing for margin negative resections. These results were seen regardless of the chemotherapeutic regimens utilized.
Variation in treatment patterns and outcomes for resected esophageal cancer at designated thoracic surgery centers.
Authors: Vaibhav Gupta, Jordan Levy, Biniam Kidane, Alyson Mahar, Jolie Ringash, Rinku Sutradhar, Gail Elizabeth Darling, Natalie Coburn
Journal: Journal of Clinical Oncology (2020)

343 Background: Ontario regionalized thoracic surgery to designated centers to provide high-volume care for patients undergoing esophageal cancer resection. The objective of this study was to assess variation in treatment patterns and outcomes across thoracic centers, and to compare their performance to non-thoracic centers. Methods: A retrospective, population-based cohort study (2002-2014) was conducted in Ontario, Canada (population 13.6 million). Adults with resected esophageal cancer were identified through the PRESTO database. Case mix, use of neoadjuvant therapy, surgical outcomes (lymph node yield and margin rates) and survival were described across thoracic centers. Multivariable regression was used to estimate the effect of having surgery at a regionalized thoracic surgery center on perioperative (in-hospital &amp; 90-day post-discharge) mortality and long-term survival, adjusting for case mix. Results: Of 3,880 patients meeting study criteria, 2,213 had pathology data available and were included in the analysis. Average age was 64 years, 85.7% had adenocarcinoma, 50.2% were pT3, and 38.4% were pN0. Most (82.6%) had surgery at one of 15 thoracic centers. Across thoracic centers, rates of neoadjuvant therapy varied 16.4-81.6%, positive margin rates varied 8.2-29.6%, median lymph node harvest varied from 7-20 nodes, perioperative mortality varied 2.6-20.5%, and 2-year survival varied from 48-80%. There was a trend toward reduced perioperative mortality, but no difference in long-term survival, with having surgery at a thoracic center. Conclusions: Even at designated thoracic centers, there is significant variability in treatment patterns, surgical outcomes, and survival. Looking beyond center volume, and translating best practices from high-performing hospitals to other hospitals, may improve patient outcomes.
Irinotecan, cetuximab, and bevacizumab (CBI) versus irinotecan, cetuximab, and placebo (CI) in irinotecan-refractory metastatic colorectal cancer (mCRC): Results from an ACCRU network randomized phase II trial.
Authors: Marla Lipsyc-Sharf, Fang-Shu Ou, Matthew B. Yurgelun, Douglas Adam Rubinson, Deborah Schrag, Shaker R. Dakhil, Philip J. Stella, Douglas Jay Weckstein, Donald B. Wender, Meredith Gail Faggen, Tyler Zemla, Erica N. Heying, Samantha R Schuetz, Stephanie Noble, Jeffrey A. Meyerhardt, Tanios S. Bekaii-Saab, Charles S. Fuchs, Kimmie Ng
Journal: Journal of Clinical Oncology (2020)

102 Background: Combination irinotecan and cetuximab is approved for irinotecan-refractory mCRC; it is unknown if the addition of bevacizumab would improve outcomes. We studied the efficacy and safety of CBI compared with CI in patients (pts) with RAS wildtype, irinotecan-refractory mCRC. Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, pts with RAS wildtype mCRC and no prior anti-epidermal growth factor receptor therapy who failed at least 1 irinotecan-based chemotherapy regimen and received bevacizumab in at least 1 prior line of therapy were randomized 1:1 to irinotecan 180 mg/m2 (or previously tolerated dose), cetuximab 500 mg/m2, and bevacizumab 5 mg/kg vs CI every 2 wks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression free survival (PFS). Multivariable Cox proportional hazard models stratified by number of prior lines of therapy and bevacizumab receipt in immediate prior line were performed. Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). The study was closed early in January 2018 for reasons related to accrual and funding after enrollment of 36 out of a planned 60 pts. Results: Between July 2015 and December 2017, 36 pts were randomized (19 to CBI, 17 to CI). 34 pts (94%) were treated with 2 or more prior chemotherapy regimens. Baseline characteristics were similar between arms. Median PFS was 9.7 vs 5.5 mo for CBI and CI arms, respectively (log-rank P =0.76; multivariable HR = 0.64; 95% CI, 0.25-1.66). Median OS was 19.7 vs 10.2 mo for CBI and CI (log-rank P= 0.04; multivariable HR = 0.41; 95% CI, 0.15-1.09). ORR was 37% for CBI vs 12% for CI ( P =0.13). Grade 3 or higher AEs occurred in 47% of pts receiving CBI vs 35% for CI ( P =0.46). Conclusions: In this prematurely discontinued trial, there were non-significant increases in PFS and ORR and a statistically significant 9.5 mo increase in median OS in favor of CBI compared to CI. Further investigation of CBI for treatment of irinotecan-refractory mCRC is warranted. Clinical trial information: NCT02292758.
Overall survival of cetuximab administered every two weeks versus weekly in real-world data of U.S. patients with metastatic colorectal cancer.
Authors: Chris Pescott, Michael Batech, Emmanuelle Boutmy, Philippe Ronga, Francois-Xavier Lamy
Journal: Journal of Clinical Oncology (2020)

23 Background: Cetuximab (CET) administered weekly (q1w) at 250 mg/m², after an initial dose of 400 mg/m², is approved in combination with chemotherapy (CT) for the treatment of (K) RAS wild-type metastatic colorectal cancer (mCRC). The use of CET 500 mg/m 2 administered with CT every 2 weeks (q2w) is according to US clinical practice guidelines and observed routinely. In this study, we compared q2w vs q1w regimens on overall survival (OS) in a presumed first-line (1L) treatment subcohort and present updated data on the noninferiority of q2w vs q1w in line-agnostic (1L+) treatment using US real-world data. Methods: Using IBM MarketScan, a large US insurance claims database, we classified a cohort of mCRC patients treated between 07/2010 and 12/2016 with CET+CT as q1w or q2w based on observed infusion patterns. Absence of mCRC-related treatment claims preceding CET initiation date (defined as the index date) qualified as CET treated in 1L. A validated algorithm was used to determine patient death. Confounding was accounted for using high-dimensional propensity scoring (hdPS) with inverse probability of treatment weights. OS was compared using Cox proportional hazards regression. Imbalanced confounders after hdPS were added to the Cox model. In 1L+, noninferiority of the q2w regimen was tested with a margin hazard ratio (HR) of 1.25. However, noninferiority could not be tested in 1L due to the small sample size; a test for difference was used instead. Results: Of 2,730 CET-exposed mCRC patients (updated), 1,779 (65.2%) and 951 (34.8%) were classified in q1w and q2w groups, respectively, among which 557 (31.3%) and 316 (33.2%) received CET in 1L. The HR (95% CI) for OS of q2w vs q1w in 1L was 1.10 (0.92-1.31; crude), and 1.05 (0.86-1.29; adjusted; p for difference: 0.625). In 1L+, crude and adjusted HRs were 1.05 (0.94-1.18) and 0.94 (0.85-1.03), respectively, rejecting the inferiority hypothesis at p &lt; 0.001. Conclusions: Only a third of patients received CET in 1L in this study. OS was statistically noninferior in q2w vs q1w in 1L+, and adjusted results in 1L suggest no differences between both treatment schedules. However, more data would be needed to formally test the noninferiority hypothesis in 1L.
Hypersensitivity reactions with allopurinol and febuxostat: a study using the Medicare claims data
Authors: Jasvinder A. Singh, John D. Cleveland
Journal: Annals of the Rheumatic Diseases (2020)

Objective To assess the risk of hypersensitivity reactions (HSRs) with allopurinol and febuxostat in a population-based study. Methods We used the 5% Medicare beneficiary sample (≥65 years) from 2006 to 2012 to identify people with a newly filled prescription for allopurinol, febuxostat or colchicine. We used multivariable-adjusted Cox regression analyses to compare the hazard ratio (HR) of incident HSRs with allopurinol or febuxostat use versus colchicine use; separate analyses were done in people exposed to allopurinol. Propensity-matched analyses (5:1) compared hazards with allopurinol versus febuxostat. Results Crude incidence rates of HSRs were as follows: allopurinol, 23.7; febuxostat, 30.7; and colchicine, 25.6 per 1000 person-years. Compared with colchicine, allopurinol, febuxostat and febuxostat+colchicine were associated with significantly higher HRs of HSRs, 1.32 (95% CI: 1.10 to 1.60) and 1.54 (95% CI: 1.12 to 2.12) and 2.17 (95% CI: 1.18 to 3.99), respectively. In propensity-matched analyses, febuxostat did not significantly differ from allopurinol; HR for HSRs was 1.25 (95% CI: 0.93 to 1.67). Compared with allopurinol start dose &lt;200 mg/day, allopurinol start dose ≥300 mg/day, diabetes and female sex were associated with significantly higher hazard of HSRs, 1.27 (95% CI: 1.12 to 1.44), 1.21 (95% CI: 1.00 to 1.45) and 1.32 (95% CI: 1.17 to 1.48), respectively. The majority (69%) of HSRs occurred in the outpatient setting. Conclusions Compared with colchicine, allopurinol and febuxostat similarly increased the risk of HSRs. Allopurinol and febuxostat did not differ from each other. In allopurinol users, starting dose, female sex and diabetes increased this risk, findings that need further study.
Regenerative lineages and immune-mediated pruning in lung cancer metastasis
Authors: Ashley M. Laughney, Jing Hu, Nathaniel R. Campbell, Samuel F. Bakhoum, Manu Setty, Vincent-Philippe Lavallée, Yubin Xie, Ignas Masilionis, Ambrose J. Carr, Sanjay Kottapalli, Viola Allaj, Marissa Mattar, Natasha Rekhtman, Joao B. Xavier, Linas Mazutis, John T. Poirier, Charles M. Rudin, Dana Pe’er, Joan Massagué
Journal: Nature Medicine (2020)