bluuebunny/crossref_metadata_2025 huggingface dataset:
Resection rate of locally advanced pancreatic cancer in gemcitabine plus nab-paclitaxel versus FOLFIRINOX.
Authors: Sharif Shahriar , Zureikat Amer H. , Novelli Paula M. , Lopez Charles D. , Kardosh Adel , Chung Ki Y. , Jones Wesley B. , Hatoum Hassan , Meredith Kenneth Lee , Zervos Emmanuel E. , Ucar Antonio , Gandhi Ripal T , Nazemzadeh Reza , Kasi Pashtoon Murtaza , Vandestraeten Erik , Decaestecker Jochen , Delaunoit Thierry , Li Charles Charles , Agah Ramtin , Pishvaian Michael J.
Published: January 2021

381

Background: There is no established treatment for locally advanced pancreatic cancer (LAPC), but by utilizing the regimens approved for metastatic pancreatic cancer, hope remains for rendering tumors resectable with chemotherapy. In this context, we looked at the resection rate in patients receiving gemcitabine plus nab-paclitaxel (Gem-Nab) in a prospective trial of patients with LAPC. Methods: TIGeR-PaC is an ongoing phase III clinical trial, studying the role of intra-arterial Gemcitabine (IA-Gem) in LAPC. The trial is designed with an induction phase where patients receive 3 cycles of Gem-Nab and a cycle of radiation after which they are randomized to IA-Gem or continuing with 4 cycles of Gem-Nab. We studied the resection rate in patients receiving Gem-Nab during induction who had subsequently continued receiving Gem-Nab post-randomization. Results: As of July 2020, 80 patients have been enrolled in the study. From this report, 30 patients were excluded because they had not completed induction and/or active treatment or were randomized to IA-Gem at the time of analysis. From the remaining 50 patients, 5 underwent resection for an overall resection rate of 10%. The median age for the total cohort was 67 years (range 47-83). Most of the resections were performed on the younger cohort of patients under 65 years (median age 60, range 47-65) in whom the resection rate was 4 out of 22 (18.2%). Conclusions: In the younger cohort of patients, TIGeR-PaC results are in line with the 15% resection rate in the LAPACT trial of patients with median age of 65 years, as reported by Phillip et al., 2020. In the TIGeR-PaC study the resection rate for LAPC treated with Gem-Nab was 10% overall, and 18.2% for younger patient population. These resection rates are comparable to the other reports for Gem-Nab and are similar to retrospective reports for the younger patients undergoing resection after treatment with FOLFIRINOX. Clinical trial information: NCT03257033.
Efficacy and safety of liposomal irinotecan plus fluorouracil/leucovorin after progression on conventional irinotecan-containing chemotherapy for metastatic pancreatic adenocarcinoma.
Authors: Bang Kyunghye , Cheon Jaekyung , Jeong Jae Ho , Im Hyeon-Su , Kim Kyu-Pyo , Ryoo Baek-Yeol , Yoo Changhoon
Published: January 2021

382

Background: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has demonstrated its clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on prior gemcitabine-based chemotherapy. However, its role in patients who previously treated with conventional irinotecan has not been investigated. We analyzed clinical outcomes of nal-IRI + 5-FU/LV in mPAC patients after progression on conventional irinotecan-containing chemotherapy. Methods: In this multicenter retrospective analysis, a total of 35 patients with mPAC who received nal-IRI + 5-FU/LV after progression on irinotecan-containing regimen, between January 2017 and March 2020, were included. The ratio of time-to-progression (TTP) with nal-IRI + 5-FU/LV to TTP with conventional irinotecan (TTPr) was correlated with duration and cumulative dose of prior conventional irinotecan. Results: The median age was 58 years (range, 35-73) and 16 patients (46%) were male. All patients received prior irinotecan as the component of FOLFIRINOX. The median duration of prior irinotecan was 4.6 months (range, 0.5-16.8) and median cumulative dose of prior irinotecan was 1230 mg (range, 150-4650). Objective response rate of nal-IRI + 5-FU/LV was 2.9% (1 partial response) and stable disease was achieved in 31.4% (n = 11). With median follow-up duration of 9.2 months [95% CI, 7.8-10.5], the median PFS and OS were 2.0 months [95% CI, 1.4-2.6] and 4.4 months [95% CI, 3.6-5.7], respectively. 6-month PFS rate was 16.3% and OS rate was 37.5%. The median TTPr was 0.41 (range 0.07-2.07) and this showed negative correlation between cumulative dose of prior irinotecan (R = -0.37, p = 0.041). There was a tendency for the negative correlation between TTPr and duration of prior irinotecan (R = -0.35, p = 0.062). Most common grade 3-4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusions: Nal-IRI + 5-FU/LV showed only modest efficacy for mPAC patients who progressed on conventional irinotecan-containing chemotherapy. Cumulative dose of prior conventional irinotecan may be correlated with the efficacy of nal-IRI + 5-FU/LV.
Real-world outcomes in recurrent versus de novo metastatic pancreatic adenocarcinoma.
Authors: Miotke Laura , Nevala-Plagemann Christopher Duane , Ying Jian , Florou Vaia , Haaland Benjamin , Garrido-Laguna Ignacio
Published: January 2021

387

Background: Optimal management of patients with recurrent pancreatic ductal adenocarcinoma (PDAC) is unknown. In the clinical trials that established a survival benefit with combination chemotherapy compared to single agent gemcitabine, patients with recurrent PDAC were either excluded (PRODIGE-4) or severely underrepresented (MPACT). In this study, we evaluated clinical outcomes of recurrent PDAC patients who receive systemic therapy and compared outcomes to patients with de novo advanced PDAC. Methods: Patients diagnosed with advanced PDAC between 2014 and October of 2019 were included using the nationwide Flatiron Health EHR-derived de-identified database. Patients without a clinic visit or initiation of treatment within 90 days of diagnosis were excluded. Patients were characterized as either de novo or recurrent PDAC based on stage at diagnosis and history of surgery. Patients with recurrent PDAC were further stratified based on time to recurrent disease. Overall survival (OS) was summarized within groups via Kaplan-Meier survival estimates, and compared between groups in the context of univariable and multivariable Cox proportional hazards models. The covariates adjusted for were gender, age, race, ECOG, smoking status, primary site, CA199, albumin, lymphocytes, neutrophils and monocytes. Results: We included 5170 patients with advanced PDAC, of which 1101 (21.3%) met criteria for recurrent disease. Patients with recurrent PDAC were more likely to have tumors in the head of the pancreas (71% vs 40%, p < 0.001) and had lower median CA19-9 (92.8 vs 617, p < 0.001), compared to the de novo PDAC patients. Median OS for the recurrent group was 10.8 m (95% CI = 9.9-11.7) vs. 7.3 m (95% CI = 7.0-7.7) in the de novo group (p < 0.001, both univariate and multivariable adjusted analyses). The most common first line palliative chemotherapy in patients with recurrent disease was Nab-paclitaxel plus gemcitabine (41%) or FOLFIRINOX (21%). Patients who recurred within six months of surgery (28%) had an OS of 10.0 m (95% CI = 8.7 -11) vs. 11.6 m (95% CI 10-12, p = 0.256) in those who recurred greater than six months from surgery. Conclusions: Our data suggest that patients with recurrent disease have significantly better survival outcomes compared to patients with de novo metastatic disease. We did not observe a significant difference in survival of patients who recurred within 6 months of resection compared to those who recurred greater than six months after surgery. These data support the inclusion of patients with recurrent PDAC in clinical trials, including those who develop recurrent disease within 6 months of surgery, with appropriate stratification for these variables.
Comparison of first-line (1L) treatment (tx) patterns and overall survival by age at diagnosis among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Elias Rawad , Cockrum Paul , Surinach Andy , Wang Shu , Chu Bong Chul
Published: January 2021

388

Background: Pancreatic cancer is mostly diagnosed in patients (pts) aged ≥ 65 years and the mortality rate is the highest among older adults. As the population ages, it is expected that there will be a significant rise in the number of older pts with mPDAC but guidance regarding their management is limited as these pts are under-represented in clinical trials. The oncological care of older adults in daily practice is challenged by various age-related conditions. Therefore, a better understanding of the real-world population will help in the development of more effective tx strategies. This study describes the proportion of pts with mPDAC who were treated, the types of regimens received, and the associated survival outcomes by age at diagnosis. Methods: Data were extracted for pts diagnosed with mPDAC between Jan 2015 and Mar 2020 from the Flatiron Health database. Pts were stratified into three age groups at diagnosis: <70y, 70-79y, and ≥ 80y. The proportion of pts was evaluated who received 1L tx and the types of regimens received in the metastatic setting. ECOG performance scores (PS) at tx initiation were described. Overall survival (OS) from the start of 1L was estimated using Kaplan-Meier methods. Results: Overall, of the 8,382 pts identified, 71.3% (n=5,973) received tx. Among pts who received tx, 55.5% (n=3,313) were aged <70y at diagnosis, 33.0% (n=1,972) were 70-79y, and 11.5% (n=688) were 80y+. Among those with data available, ECOG PS ≥2 was observed in 15.9% (n=381) of pts <70y, 21.0% (n=309) of pts 70-79y, and 29.9% (n=147) of pts 80y+(p < 0.001). The proportion of pts who received tx decreased with increasing age at diagnosis: 74.9%, 70.9%, and 58.5% for pts aged <70y, 70-79y, and 80y+, respectively. Gemcitabine monotherapy (gem-mono) and gemcitabine + nab-paclitaxel (GNP) accounted for > 70% of regimens prescribed to pts aged 80y+. The median OS (mOS) for patients treated with GNP, gem-mono, FOLFIRINOX, and liposomal irinotecan-based regimens are presented in the table. Conclusions: This study of treatment patterns among pts with mPDAC found that older pts were more likely to have a decreased performance status and are less likely to receive treatment. However, older adults who received systemic therapy had comparable survival outcomes to younger pts treated with a similar regimen. The results of this large descriptive analysis suggest that the treatment strategy of mPDAC should not be based on age but rather on an overall assessment of the performance/functional status and geriatric profile of older pts. [Table: see text]
Real-world safety data and differentiation of second-line (2L) 5-fluorouracil (5-FU) based regimens among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Kim George P. , Cockrum Paul , Chudnovsky Aleksander , Surinach Andy , Wainberg Zev A. , Wang Shu , Yakubu Amin
Published: January 2021

390

Background: Chemotherapy related adverse events (AEs) can impact the treatment of patients, reducing quality of life and leading to dose delays and treatment discontinuation. This study examined the proportion of patients (pts) with mPDAC treated with 5-FU-based regimens in the 2L setting who experienced AEs during treatment. Methods: Data were extracted for pts diagnosed with mPDAC who initiated 2L treatment between January 2016 and July 2020 from the Flatiron Health electronic health database. Pts included in the study were treated with FOLFIRINOX (FFX), FOLFOX, FOLFIRI, or a regimen containing liposomal irinotecan. The occurrence of grade 3 (G3) and grade 4 (G4) neutropenia, G3/G4 elevated alanine transaminase (ALT) and anemia where transfusion was indicated were determined using lab results and the grading criteria from the Common Terminology Criteria for Adverse Events v4.03. The occurrence of diarrhea, fatigue, nausea and vomiting (N/V), and neuropathy were identified from structured diagnosis records through ICD-10-CM codes. Duration of therapy (DOT) was assessed for each regimen. Descriptive statistics for AEs and DOT were reported. Results: Of the 804 pts included in the study, 28.4% (n=228) received FFX, 39.8% (n=320) received regimens containing liposomal irinotecan, 24.8% (n=199) received FOLFOX, and 7.1% (n=57) received FOLFIRI. The median DOT (IQR) was 86 days (d) (43 – 206), 79d (41 – 169), 72d (43 – 166), and 84d (46 – 148) for pts who received FFX, liposomal irinotecan, FOLFOX, and FOLFIRI, respectively. G3/G4 neutropenia (<1000/mm3) presented in 28.1% (n=64) of pts treated with FFX, 11.9% (n=38) of pts treated with liposomal irinotecan, 17.1% (n=34) of pts treated with FOLFOX, and 36.8% (n=21) of pts treated with FOLFIRI. NV occurred in 14.9% (n=34), 13.1% (n=42), 12.6% (n=25), and 10.5% (n=6), respectively. The full AE results are summarized in the table. Conclusions: In this assessment of often dose-limiting AEs among pts with mPDAC treated in 2L, pts who received liposomal irinotecan had the lowest proportion of neutropenia. No clear pattern was noted for N/V, neuropathy, fatigue, anemia, and elevated ALT. Further research is necessary to determine the real-world cost implications of AEs in this patient population. [Table: see text]
The pattern of brain metastasis in colorectal cancer: Efficacy of metastasectomy, chemotherapy.
Authors: Goksu Suleyman Yasin , Beg Muhammad Shaalan , Sanjeevaiah Aravind , Gumusgoz Emrah , Hsieh David , Ozer Muhammet , Jones Amy Little , Kainthla Radhika , Verma Udit , Al Mutar Salwan , Olson Craig , Pogacnik Javier Salgado , Sanford Nina Niu , Kazmi Syed Mohammad Ali
Published: January 2021

40

Background: Colorectal cancer patients with brain metastases experience poor outcomes; however treatment strategies are understudied. In this study, we investigated the impact of different treatments for colorectal cancer patients with brain metastases. Methods: We identified stage 4 colorectal adenocarcinoma patients with brain metastasis using the National Cancer Database diagnosed between 2010 and 2015. Patients with unknown survival data, other histologies, and multiple primary sites were excluded. Patients with and without brain metastasis were compared using the Chi-square test. Kaplan-Meier method was performed to calculate univariable overall survival (OS). We used the Cox regression model for multivariable analysis after adjusting by age, race/ethnicity, comorbidity score, surgery, chemotherapy, and radiotherapy. Results: Among 75,901 patients with stage 4 colorectal adenocarcinoma, 1.6% had brain metastasis. Patients with brain metastasis were more likely to have bone (23% vs. 5%, p < 0.001) and lung metastasis (52% vs. 21%, p < 0.001), but less likely to have liver metastasis (56% vs. 72%, p < 0.001) compared to patients without brain metastasis. Patients with brain metastasis had higher KRAS mutation rate (54% vs. 43%, p < 0.001). Patients with brain metastasis were more likely to be age ≥ 50 years (85% vs. 83%, p = 0.01), white race (76% vs. 71%, p = 0.001), and receive radiotherapy (63% vs. 12%, p < 0.001). Total 26.4% of patients with brain metastasis underwent metastasectomy, and those patients had better OS compared to patients with non-metastasectomy (median OS 12 vs. 4 months, p < 0.001). Median OS in all patients with brain metastasis was 5.5 months. Patients with brain metastasis who received multiagent chemotherapy had improved OS compared with patients who received single-agent chemotherapy (mOS 13 vs. 6 months, p < 0.001). Patients with brain metastasis who received brain radiotherapy had better OS (mOS 6.3 vs. 3.7 months, p = 0.005) than those who did not. On multivariable analysis, metastasectomy (HR 0.65 95% CI [0.57-0.75]) and receipt of multiagent chemotherapy (HR 0.68 95% CI [0.54-0.86]) were associated with favorable prognosis, but brain radiotherapy was not (HR 1.04 95% CI [0.91-1.19]). Conclusions: Brain metastases are rare in colorectal cancer but portend poor survival. Lung and bone metastases are found more frequently in these patients. Treatment with metastasectomy or multiagent chemotherapy is associated with improved overall survival.
Projected 30-day out-of-pocket and total spending on pancreatic enzyme replacement therapy under Medicare Part D.
Authors: Gupta Arjun , Premnath Naveen , Beg Muhammad Shaalan , Khera Rohan , Dusetzina Stacie
Published: January 2021

401

Background: Pancreatic enzyme replacement therapy (PERT) can reduce symptoms of indigestion and improve nutrition in patients with exocrine pancreatic insufficiency. PERT is under-prescribed, and this may be related to actual costs and prescriber sensitivity to these costs. Thus, we aimed to assess PERT costs. Methods: We used Medicare Part D formulary and pricing files for the first quarter of 2020 to conduct a patient-level modeling study to describe point-of-sale and out-of-pocket costs for each PERT formulation among Part D stand-alone and Medicare Advantage prescription drug plans. We calculated costs across nationwide plans under three scenarios: (1) standard benefit design ($435 deductible and 25% coinsurance after the deductible is met); (2) 25% coinsurance (for fills after the deductible and in the coverage gap until the patient spends $6,350 out-of-pocket); and (3) 5% coinsurance (once catastrophic coverage is reached). PERT doses are identified by the lipase content per capsule (in United States Pharmacopeia, USP, units). We calculated the number of units for each PERT formulation/ dose form that would provide optimally dosed PERT for the average US adult (250,000 USP units of lipase per day), based on guidelines and consensus. We first calculated costs for a single unit of PERT. Next, we calculated the number of units needed daily for each formulation/ dose form to provide optimally dosed PERT, and multiplied it by 30 to generate 30-day requirements and costs. Results: Across 3,974 plans nationwide, five PERT formulations in seventeen different doses were covered by Medicare plans in 2020. The range of lipase content in a single unit ranged from 3,000 to 40,000 USP units, and the per-unit list price ranged from $1.44 to $13.89. The point-of-sale price for a 30-day supply of optimally dosed PERT ranged from $2,109 to $4,840. For patients, the expected out-of-pocket costs for a 30-day supply of optimally dosed PERT averaged $999 across formulations (range, $853 to $1536) for those paying a deductible and coinsurance, $673 (range, $527 to $1210) for fills made after meeting the deductible until reaching catastrophic coverage, and $135 (range, $105 to $242) after reaching catastrophic coverage. Conclusions: In this analysis of 2020 Medicare Part D plans, the estimated out-of-pocket cost for just a 30-day supply of optimally dosed PERT was high— at least $100 in the catastrophic phase and approximately $1,000 in the initial phase. In the setting of pancreas cancer, already associated with heavy symptom burden and distress, the financial burden from a supportive care intervention (such as PERT) has been underappreciated. These costs may serve as a barrier to Medicare beneficiary drug access and contribute to financial toxicity.
Nanoliposomal irinotecan-based chemotherapy after regular irinotecan-based chemotherapy in patients with pancreas cancer.
Authors: Smith Caleb J , Bekaii-Saab Tanios S. , Cook Kathryn , Eiring Rachel , Halfdanarson Thorvardur Ragnar , Hanna Mina Samir Erian , Jin Zhaohui , Jochum Jacob A. , Ma Wen Wee , Mitchell Jessica L , Pitot Henry C. , Jatoi Aminah
Published: January 2021

402

Background: Pancreas cancer is an aggressive malignancy with limited therapeutic options. Nanoliposomal irinotecan (Nal-IRI) is a preferred second-line treatment, and current guidelines recommend its use in the absence of prior irinotecan. This study aimed to assess whether patients who had received regular irinotecan derive benefit from Nal-IRI. Methods: Medical records of metastatic pancreas cancer patients who had received regular irinotecan and then Nal-IRI were reviewed. The following information was extracted from each medical record: patient demographics, confirmation of a diagnosis of exocrine pancreas cancer, initial cancer stage, dates of administration of the drugs of interest, adverse events that occurred with Nal-IRI treatment, reasons for stopping regular irinotecan, and reasons for starting and stopping Nal-IRI. The primary endpoint was overall survival after the initiation of Nal-IRI (an a priori threshold of > 4 months defined success). Survival data were censored based on date of last follow up. Direct quotes from the medical record were documented to provide insight on prescribing Nal-IRI when guidelines advised the contrary. Results: Sixty four patients met eligibility criteria with a median age of 65 years (range: 36, 80 years). Prior to Nal-IRI, 61 patients had received FOLFIRINOX, and 3 FOLFIRI. Of these, 32 patients manifested progressive disease on regular irinotecan-based therapy. Nal-IRI was prescribed with a fluoropyrimidine; only one patient received monotherapy. At time of analysis, 54 patients had died. Median overall survival from initiation of Nal-IRI was 5.1 months (95% confidence interval (CI): 5.6, 4.3, months). An exploratory comparison, based on no cancer progression with regular irinotecan versus progression, showed improved survival with Nal-IRI in the former group: 6.1 months (95% CI: 9.3, 5.1 months) versus 4.3 months (95% CI: 4.8, 2.3 months); p=0.0006. Nal-IRI adverse events occurred as expected. Qualitative data illustrated several themes, including “limited treatment options,” which appeared to drive the decision to prescribe Nal-IRI. Conclusions: Nal-IRI might be considered in pancreas cancer patients who had received regular irinotecan, particularly in the absence of disease progression with the latter.
Characteristics and outcomes for fecal occult blood test (FOBT) screen detected (SD) versus non-screen detected (NSD) colorectal cancer (CRC).
Authors: Mendis Shehara Ramyalini , Ananda Sumitra S , Hong Wei , Faragher Ian , Croxford Matthew , Jones Ian , Steel Malcolm , Jalali Azim , Gard Grace , To Yat Hang , Lee Margaret , Kosmider Suzanne , Wong Rachel , Tie Jeanne , Gibbs Peter
Published: January 2021

42

Background: FOBT based screening for CRC has been shown in multiple studies to reduce CRC mortality. Beyond the well described earlier stage at diagnosis, other characteristics of SD cancers have not been well studied. Since 2006 Australians aged 50-74 have regularly been mailed an immunochemical FOBT via the National Bowel Cancer Screening Program (NBCSP), with participation rate stable around 40%. Methods: To explore patient (pt), tumour, treatment and outcome data for SD compared to NSD, we examined a multi-site CRC database where prospectively collected data includes method of detection. Categories include SD via the NBCSP, cases that were symptomatic or incidentally found on imaging (NSD), and cases detected by screening outside the NBCSP (OSD). High risk features for Australian Clinicopathological Staging System (ACPS) Stage B included emergency presentation, T4, lymphovascular invasion and <12 lymph nodes examined. Results: Of 6969 registry pts diagnosed 06/2006–06/2020, 4107 (59%) were aged 50-74, including 473 (12%) SD, 3228 (79%) NSD and 406 (10%) OSD. SD versus NSD pts were younger (mean 62.4 v 64.2 years), had better ASA score (ASA 1-2: 79% v 66%, Odds Ratio [OR] 1.9, p<0.001), earlier stage at diagnosis (ACPS A/B/C/D = 38%/21%/28%/5% v 17%/29%/26%/21%, p<0.001), were more often left-sided (41% v 33%, OR 1.44, p<0.001) but less frequently located in the rectum (28% v 36% OR 0.70, p=0.001). There was no difference by gender. SD tumors were more often well/moderately differentiated (76% v 66%, OR 1.65, p<0.001) and less often mucinous (16% v 20%, OR 0.66, p=0.002). SD stage A tumours were more often T1 (66% v 43%, OR 0.36, p<0.001). SD stage B tumours were more often T3 (92% v 85%, OR 0.43, p=0.033), and had fewer high risk features (60% v 49%, OR 0.64, p=0.036). SD stage C pts had a similar rate of N2 disease (25% v 31%, p=0.20), but more often received adjuvant chemotherapy (96% v 86%, OR 3.6, p=0.002). De novo stage D and relapsed SD pts more often underwent metastatic resection (46% v 25%, OR 2.6, p<0.001). Relapse free survival (RFS) in stage A-C, progression free survival in stage D (PFS), and overall survival (OS) was superior for SD and is in Table. Conclusions: We show for the first time to our knowledge that SD CRCs have many distinct and favourable prognostic features that appear to be driving favourable stage based outcomes when compared to NSD patients. This prognostic data could inform adjuvant therapy decision making and surveillance strategies for SD CRC. [Table: see text]
Olaparib sensitivity observed in metastatic pancreatic cancer (mPaC) with a wide spectrum of germline BRCA1 and BRCA2 mutations (gBRCAm).
Authors: Golan Talia , Kindler Hedy L. , Schatz Philipp , Goranova Teodora , Locker Gershon Y. , Cui Karen , Schlienger Katia , McGuinness David , Williams J. Andrew , Orr Maria , Gutjahr Thorsten , Liu Yu-Zhen
Published: January 2021

420

Background: The POLO study (NCT02184195) showed that mPaC patients (pts) with a deleterious or suspected deleterious gBRCAm, and whose disease had not progressed during ≥16 weeks of first-line platinum-based chemotherapy, had significantly longer progression-free survival (PFS, primary endpoint) with maintenance olaparib vs placebo: median 7.4 vs 3.8 months, hazard ratio (HR) 0.53; P= 0.004. PFS benefit was observed in pts with g BRCA1m (HR 0.40) and g BRCA2m (HR 0.63). The POLO study represents the largest BRCAm prevalence study in pancreatic cancer . We report additional exploratory analysis to further characterize patient gBRCAm profiles, including the relationship with efficacy. Methods: Pts were enrolled based on either a previously identified gBRCAm status from a local test result and subsequently confirmed by central testing, or a prospectively identified gBRCAm. Pts received maintenance olaparib 300 mg twice daily (tablet) or placebo. PFS was assessed by blinded independent central review (modified RECIST v1.1). Results: Of 3194 prospectively screened pts, a valid BRCA test result was obtained for 3175 (99%) from 12 countries; gBRCAm prevalence was 6.2% in pts not previously known to harbor a gBRCAm (196/3175; 1.6% g BRCA1m, 4.5% g BRCA2m). In countries (n = 8) with > 100 pts prospectively tested, highest gBRCAm prevalence was 9.2% (USA) and lowest 4.0% (Spain). Prevalence by race ( > 100 pts); 6.4% Caucasian, 4.6% Asian. In total, 154 pts with a gBRCAm satisfied all eligibility criteria and were randomized (106 prospectively tested and 48 by local test [44/48 subsequently confirmed by Myriad testing]). 37/154 (24%) randomized pts carried a common Ashkenazi Jewish founder mutation, the majority being from Israel (21 pts). From a total of 151 variants, frameshift mutations were most frequent (g BRCA1m 69.6%, g BRCA2m 71.4%) followed by nonsense mutations (g BRCA1m 6.5%, g BRCA2m 17.1%). The efficacy (PFS) of olaparib vs placebo in the different subgroups are shown in the table. Conclusions: In pts with mPaC enrolled in POLO, g BRCA2m were more prevalent than g BRCA1m and mutation type was predominantly frameshift. PFS benefit was consistent across a heterogenous spectrum of gBRCAm and with the previously reported full analysis set. Clinical trial information: NCT02184195. [Table: see text]
Molecular profiling of advanced pancreatic ductal adenocarcinoma (PDAC): Role of ctDNA.
Authors: Lamarca Angela , McNamara Mairead Geraldine , Hubner Richard , Valle Juan W.
Published: January 2021

425

Background: Molecular profiling of tumour samples and circulating tumour DNA (ctDNA) may inform treatment of advanced cancer; the role of ctDNA to predict progression-free-survival (PFS) and overall survival (OS) in advanced PDAC is not fully understood. Methods: Eligible patients: those diagnosed with advanced PDAC undergoing molecular profiling [tumour (Foundation Medicine CDx/Caris) or ctDNA (FoundationMedicine Liquid (72 cancer-related genes))]. Baseline patient characteristics and molecular profiling outcomes, including mutant allele frequency (MAF) for pathological alterations were extracted. The primary aim was to assess the impact of presence of ctDNA at time of systemic chemotherapy initiation on PFS and OS. Results: Total of 26 samples (ctDNA 18 samples and 8 tumour samples) from 25 patients diagnosed with advanced PDAC underwent molecular profiling. When the whole population was analysed, the rate of sample analysis failure seemed to be higher when tumour tissue was tested (37.5%) compared to ctDNA (5.56%); p-value 0.072. The overall rate of identification of pathological findings was 72.73%, with 18.18% of patients having targetable findings [EGFRmut (1 patient), KRAS G12C mut (1 patient), FGFR2 fusion (1 patient), RNF43 mut (1 patient)]; these findings impacted treatment management in one patient only (RNF43 mutation; Wnt inhibitor). Variants of unknown significance were identified in 63.64% of samples. Patients with ctDNA analysis at time of palliative chemotherapy initiation (16 samples; 15 patients) were analysed [6 female (40.00%), median age 69.57 years (range 51.61-81.49), metastatic disease (66.67%), 80% first-line (80%), 20% second-line]. Pathological mutations were identified in 9/15 (60.00%) of these patients (KRAS mutation identified in 6/9). After median follow-up of 8.33 months from sample acquisition, 80% and 53.33% of patients had progressed and died, respectively. Median estimated PFS and OS were 5.65 months (95% CI 1.59-8.17) and 7.80 months (95% CI 4.13-not reached). Presence (vs absence) of pathological alterations in ctDNA showed a trend towards shorter PFS (2.91 vs 6.51 months; HR 1.38 (95% CI 0.40-4.77)) and OS (6.12 vs 9.72 months; HR 2.03 (95% CI 0.60-6.82)). Conclusions: This pilot study demonstrates the feasibility of ctDNA analysis in patients with advanced PDAC prior to initiation of palliative therapy. The presence of pathological alterations in ctDNA may prognosticate for worse PFS and OS. Larger studies are required to confirm these findings.
The use of elevated circulating hepatocyte growth factor (HGF) level as a potential prognostic biomarker in locally advanced pancreatic cancer.
Authors: Roberts Hannah Johnson , Wo Jennifer Yon-Li , Yeap Beow Y. , Ulysse Christine A. , Murphy Janet E. , Weekes Colin D. , Ryan David P. , Clark Jeffrey William , Ferrone Cristina R. , Lillemoe Keith D. , Qadan Motaz , Fernandez-del Castillo Carlos , Jain Rakesh K. , Hong Theodore S. , Duda Gabriel Dan
Published: January 2021

429

Background: The hepatocyte growth factor (HGF)/c-MET pathway has pleiotropic functions in tumor progression including invasion and cancer cell survival. The potential use of circulating plasma HGF as a prognostic biomarker is not known. Methods: This was an analysis of plasma HGF in patients enrolled in a single arm phase II study (NCT01821729) of patients with previously untreated locally advanced pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX and losartan followed by chemoradiotherapy before resection was attempted (Murphy JE et al., 2019). Eligible patients from the trial included those who had undergone baseline research labs including HGF. Circulating HGF was measured in the plasma on day 1 of treatment using ELISA, and the median value was used to define high vs low levels for the purpose of analysis. The association of elevated HGF with overall survival (OS) was analyzed by univariable and multivariable Cox regression, adjusting for tumor size (≤ versus > 40 mm) and serum CA19-9 (≤ versus > 37 U/mL). Results: There were 46 eligible patients with a median follow up of 31 months. The median age was 63 (range 42-78) and 52% were female (24/46). Median tumor size was 41.4 mm (range 18–68 mm). There were 41/46 patients (89.1%) with elevated baseline CA19-9. Median baseline HGF was 1,250.55 pg/mL (range 650.9–6,459.1). Median OS was 38.4 months for patients with baseline HGF at or below the median, and 19.3 months for those with elevated HGF. On univariate analysis, elevated HGF was associated with poorer OS (HR 2.28, 95% CI 1.06–4.87, p = 0.03). On multivariate analysis, after controlling for tumor size and baseline CA19-9, elevated plasma HGF remained significantly associated with poorer OS (HR 2.58, 95% CI 1.16–5.70, p = 0.02). Conclusions: In conclusion, elevated baseline circulating plasma HGF is an independent biomarker of poorer OS in patients with locally advanced PDAC treated with neoadjuvant therapy. Further randomized studies are needed to define the negative predictive biomarker value for high plasma HGF and identify the optimal HGF range as well as determine applicability to other stages of disease. These results support the continued investigation of plasma HGF in ongoing clinical trials with PDAC patients.
Impact of KRAS alterations in localized pancreatic cancer (PC).
Authors: Shreenivas Aditya Varnam , Annunzio Kaitlin , Kamgar Mandana , Chakrabarti Sakti , Thomas James P. , Madhavan Srivats , Dua Kulwinder , Khan Abdul H. , Hall William Adrian , Erickson Beth , Christians Kathleen K. , Clarke Callisia , Evans Douglas B. , Tsai Susan , Szabo Aniko , Urrutia Raul , Zimmermann Michael T , Reddi Honey V , George Ben
Published: January 2021

431

Background: Patients (pts) with localized PC do not routinely undergo comprehensive genomic profiling (CGP) unless they develop recurrent or metastatic disease. KRAS is the most frequently mutated gene in PC, however, the impact of different KRAS mutations in localized PC has not been well characterized. We interrogated our genomic database to analyze the KRAS status in PC pts who presented with localized disease at diagnosis (Dx). Methods: We identified PC pts at our institution who underwent CGP utilizing the Foundation One CDx assay and had localized disease at initial Dx; these pts were categorized into resectable/borderline resectable PC (LPC) and locally advanced PC (LAPC). All pts with LPC and LAPC underwent neoadjuvant chemotherapy and chemoradiation prior to possible surgery (all intended therapy - AIT). Tissue from metastatic sites was used for CGP in pts who developed recurrent/metastatic disease before or after completion of AIT. The primary tumor was used for CGP in pts who completed AIT without subsequent relapse or in the absence of adequate metastatic tissue. Effect of each gene on response and survival outcomes was estimated using proportional odds and Cox regression analysis, respectively, adjusting for stage. Results: 75 pts were identified, median age at Dx was 65 years, 59% were male, 65% had a primary tumor in the pancreatic head. 38 (86%) pts with LPC completed AIT compared to 21 (68%) pts with LAPC (p<0.001). KRAS mutation was detected in 95% (71/75) of pts– 94% (67/71) in codon 12 and 6% (4/71) in codon 61. The various KRAS mutations and their association with completion of AIT is summarized in the table. The likelihood of completing AIT did not differ based on KRAS wildtype (WT) vs mutated status (p =1.00), the mutated codon (codon 12 vs. codon 61; p =1.00) or the individual KRAS point mutations (p = 0.7); however, all patients with G12A (N= 1), G12C (N=1), G12L (N=1) and G12R (N=11) mutations completed AIT. KRAS status (mutated vs. WT) and the individual KRAS mutations were not associated with overall survival (OS) after adjusting for stage (p= 0.13 and p = 0.26 respectively). Median OS for patients with LPC and LAPC, was 39 months (mos) and 29 mos respectively. Conclusions: KRAS status and individual KRAS mutations did not have an impact on completing AIT or mOS; however, these findings need to be interpreted with caution due to the inherent biases involved in such analyses. The clinical significance and functional relevance of KRAS G12A, G12C, G12L and G12R mutations, though relatively rare, needs further characterization as well as mechanistic elucidation. [Table: see text]
Development and validation of a radiomics nomogram to discriminate advanced pancreatic cancer patients with liver metastases or other metastatic patterns.
Authors: Hang Junjie , Wu Lixia
Published: January 2021

435

Background: Pancreatic cancer patients with liver metastases had much poorer prognosis than those with other metastatic patterns. This study aimed to develop and validate a radiomics model to discriminate pancreatic cancer patients with liver metastases from patients with other metastatic patterns. Methods: We evaluated 77 patients advanced pancreatic cancer (APC) with different metastatic patterns and performed texture analysis on the region of interest (ROI). 58 patients and 19 patients were allocated randomly into the training cohort and the validation cohort with almost the same proportion of patients with liver metastases. An independent samples t-test was used for initial feature selection in the training cohort. Random Forest Classifier (RFC) was used to construct models based on these features in both cohorts and a radiomics signature (RS) was derived from the model. Then a nomogram was constructed based on RS and CA19-9, and validated with calibration plot and decision curve. The prognostic value of RS was evaluated by Kaplan-Meier methods. Results: A nomogram based on the RS and CA19-9 was constructed and it demonstrated good discrimination in the training cohort (AUC = 0.93) and validation cohort (AUC = 0.81). Kaplan-meier methods showed that patients with RS>0.61 had much poorer OS than patients with RS < 0.61 in both cohorts. Conclusions:This study presents a radiomics nomogram incorporating both RS and CA19-9, which can be used to discriminate advanced pancreatic cancer patients with liver metastases from patients with other metastatic patterns.
Second primary cancers in patients with sporadic deficient mismatch repair (dMMR) colorectal cancer (CRC).
Authors: Alidina Ayman , Lipton Lara Rachel , Gately Lucy , Skinner Iain , Mendis Shehara Ramyalini , Hong Wei , Dunn Catherine , Cho Jin , To Yat Hang , Steel Malcolm , Jones Ian , Lee Margaret , Tie Jeanne , Kosmider Suzanne , Wong Rachel , Yeung Justin , Gibbs Peter
Published: January 2021

45

Background: Patients with hereditary non polyposis colorectal cancer (HNPCC) diagnosed with CRC have an elevated risk of a second primary CRC (SPCRC) and of rapid primary cancer development. This informs both initial surgical approach and endoscopic surveillance intervals. A feature of HNPCC is dMMR, also found in 15% of sporadic CRC, where the risk of SPCRC has yet to be defined. Methods: We examined a multi-site comprehensive CRC database (Melbourne, Australia), where prospectively collected data includes family history (including HNPCC), histology, surgery performed and incidence of second primary cancer. Sporadic dMMR included any case with a BRAF V600E mutation, confirmed hypermethylation, negative germline testing, or age over 60 years. We explored the incidence and timing of SPCRC in patients with early stage sporadic dMMR (or MSI-H) versus pMMR cancers. Results: From February 2004 to December 2019, 7442 patients diagnosed with stage I-III CRC were recorded. MMR status was known in 4079 (54.8%), including 714 with dMMR colorectal cancer (17.4%) of which 575 (14.6%) were deemed sporadic dMMR. Sporadic dMMR patients were older (mean 76.2 years vs 65.9 years, p = < 0.001), more likely to be female (65.2% vs 42%, p = < 0.001) and have a right sided primary (80.9% vs 32.8%, p = < 0.001), compared to patients with pMMR CRC. A SPCRC was diagnosed in 11/575 patients (1.91%) with sporadic dMMR CRC versus 27/3365 (0.83%) patients with pMMR CRC (HR = 2.57, 95% CI 1.28 - 5.17, p = 0.008). Median time to SPCRC was 1.13 years vs 2.38 years (p = 0.49). The SPCRC diagnosed in sporadic dMMR CRC vs pMMR CRC were more likely to be dMMR ((72.7%) vs (25.9%), p = 0.03), but a similar number were stage I or II ((81.8%) vs (81.5%)) and a similar number were surveillance detected ((72.7%) vs (77.8%). Conclusions: Patients with sporadic dMMR appear to have a significantly elevated risk of SPCRC compared to the pMMR population and were diagnosed at a shorter interval. The SPCRC is also more likely to also be dMMR. Increased colonoscopic surveillance of patients presenting with an initial sporadic dMMR cancer should be considered where clinically appropriate.
COVID-19 infection in gastrointestinal (GI) cancer patients receiving systemic anticancer treatment (SACT) during the outbreak of the pandemic: The Guy's Cancer Centre experience.
Authors: Tsotra Eirini , Gousis Charalampos , Russell Beth , Moss Charlotte , Palmer Kieran , Montes Ana , Maisey Nicholas R. , Rigg Anne , Owczarczyk Kasia , Qureshi Asad , Harris Victoria , Ross Paul J. , Sarker Debashis , Thillai Kiruthikah , DeNaurois Julien , Roca Jose , Ngan Sarah , Van Hemelrijck Mieke , Sita-Lumsden Ailsa , Dolly Saoirse
Published: January 2021

455

Background: The COVID-19 pandemic has prompted difficult decisions around the use of SACT. These were based on limited early data suggesting cancer patients receiving SACT were at an increased risk of COVID-19 severe infection and death. Our study aim was to identify the COVID-19 infection and mortality rates of GI cancer patients receiving SACT. Methods: All GI patients receiving SACT at Guy’s Cancer Centre between March, and May 31, 2020 were included. Demographic data (age, ethnicity, socio-economic status (SES)) and cancer characteristics (stage, SACT type, intent and treatment-line) were collected. COVID-19 infection was confirmed by PCR and severity defined by the World Health Organisation (WHO) classification. Patients with clinical or radiological diagnosis alone were excluded. Results: Of 417 GI patients receiving SACT during the study period, 345 (82.7%) received chemotherapy (alone or combined with targeted/biological treatment), 68 (16.3%) targeted/biological treatment alone and 4 (1%) immunotherapy. 14 (3.4%) patients were diagnosed with COVID-19, 13 were on chemotherapy and 1 on targeted/biological treatment. Commonest cancers in the COVID-19 positive group were colorectal (57.1%) and hepatobiliary (21.4%), followed by oesophago-gastric (14.3%) and neuroendocrine tumours (7.1%); 57.1% had stage IV disease. 64.3% of the positive patients were male (compared to 57.3% in the COVID-19 negative population), mean age was 57.7 years (63.1 years) and 85.7% had low SES (79.7%). 8 (57.1%) patients had severe infection and there were 3 (21.4%) COVID-19 related deaths. All the patients who died from COVID-19 were male and were receiving palliative chemotherapy. Only one patient was neutropenic (grade 1) when diagnosed with COVID-19. Conclusions: The rate of COVID-19 infection in our population was relatively low (3.4 %). Of the 14 COVID-19 positive patients, 57.1% had severe infection, 21.4% died (compared to 3.7% mortality in the non-infected group) and all but one were on chemotherapy. This prospective data, from a large UK comprehensive Cancer Centre, provides some evidence that continuing SACT through the pandemic is relatively safe. The risk of COVID-19 related infection and death must be off-set against the cancer-related morbidity and mortality associated with treatment delays.
Deploying an AI-based online search tool to increase patients’ access to and understanding of solid tumor GI clinical trials.
Authors: Kasi Pashtoon Murtaza , Jordan Emily , Jahreiss Luca
Published: January 2021

456

Background: The number and complexity of clinical trials has been growing, making finding and accessing trials increasingly challenging. Additionally, the goal of representative trial populations remains elusive with sometimes devastating medical consequences. A key barrier to increasing recruitment efficiency is patients’ low awareness of clinical trials as an option. They rarely hear about trials from their oncologists, unless they are based at a research center, which introduces trial population biases by including only patients with good healthcare access. And even if patients decide to search for information on trials themselves, the information is difficult to understand. There are existing trial search tools, but they have multiple shortcomings: complex navigation, limited search functionality, clinical trial data is too complex for non-specialists to understand, and lack of clarity on next steps. Methods: Access to trials via a novel trial search tool (www.ancora.ai) which uses AI to restructure trial information was the main focus of this study. For increased GI cancer specificity, 6 key GI cancers were included into the AI model and information was restructured based on key eligibility differentiators identified (see data structure table). Research participants (xx GI oncology patients) were recruited with the support of patient associations (e.g. The Colon Club) leveraging social media. They were asked to complete a 20 minute survey evaluating both an established tool (clinicaltrials.gov) and the novel tool to find trials relevant for them. They had to assess different aspects of the tools’ usability on a 5-level Likert scale. Survey results were analyzed in MS Excel, using built-in statistical functions (mean, standard deviation, student’s t-test). Results: Please note the survey is ongoing and results will be updated. Current survey respondents had a base level of awareness of clinical trials (3.1±1.2), with patient associations and the internet as leading information sources. The novel tool seemed to make it easier to find trials (3.7±0.9 vs. 2.7±1.3), showed an improvement in ease of understanding information presented (3.8±1.1 vs. 2.6±1.3) and directionally provided more clarity on what next steps towards trial enrollment would be (4.2±0.8 vs. 3.7±1.4). Overall, this led to higher patient satisfaction (3.4±1.1 vs. 2.3±0.5). Conclusions: Novel patient-focused, AI-driven clinical trial support tools can unlock trial access for all patients. Democratizing trial information will not only increase trial accrual, but also patient satisfaction while reducing disparities. [Table: see text]