McWilliams, Robert R.

Abstract Background: Pancreatic cancer (PC) ranks among the top causes of cancer mortality. Risk stratification is an important step toward prevention and early detection. Prior work has shown that ABO blood type (non-O) and first-degree family history of PC are associated with increased PC risk. Individuals with first-degree family history of PC have a 2- to 3-fold increased risk, but it is unclear if ABO blood type plays a role in the familial aggregation of PC. We investigated PC risk among first-degree relatives (FDRs) of PC probands based on the probands' serologic blood type (O vs non-O). Methods: A total of 702 probands sequentially enrolled in the Mayo Clinic Pancreas Research Registry from 2000-2016 with serologic ABO blood type provided information on family history of cancer for 5,178 FDRs. FDRs were grouped based on their related probands' blood type as type O (n=242; 1,768 FDRs) vs non-O (n=460; 3,410 FDRs). Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing the number of PC cases observed among FDRs to those expected using data from the Surveillance, Epidemiology and End Results (SEER) Program as the reference population. SIRs for PC risk were calculated separately for FDRs of probands with type O vs FDRs of probands with non-O blood, and stratified by sex of FDRs and relationship to proband (parent, sibling, or offspring). Results: Compared to the SEER reference, PC risk was nearly 2-fold higher among FDRs of PC probands (SIR=1.76; 95%CI: 1.35-2.26). When stratified by probands' ABO type, risk for PC was higher among FDRs of probands with non-O blood (SIR=1.94; 95%CI: 1.41-2.60), compared to FDRs of probands with O blood (SIR=1.42; 95%CI: 0.83-2.28). Parents of probands with non-O blood had increased PC risk (SIR=3.28; 95%CI: 2.18-4.74, n=920), but not parents of probands with O blood (SIR=1.75; 95%CI: 0.75-3.45, n=484), p-value for between-group difference=0.10. Among FDRs of probands with O blood, female FDRs had increased PC risk (SIR=2.12; 95%CI: 1.06-3.79), but male FDRs did not (SIR=0.86; 95%CI: 0.31-1.88). Higher PC risk was observed among female FDRs of probands with non-O blood (SIR=2.28; 95%CI: 1.44-3.41) than male FDRs of probands with non-O blood (SIR=1.62; 95%CI: 1.00-2.48). Mothers of probands with O blood had increased PC risk (SIR=2.89; 95%CI: 1.05-6.28) compared to fathers (SIR=0.79; 95%CI: 0.09-2.84). Both mothers (SIR=3.60; 95%CI: 1.96-6.03) and fathers (SIR=2.95; 95%CI: 1.61-4.95) of probands with non-O blood had increased PC risk. No major findings were observed among probands' siblings or offspring. Conclusions: PC risk is greater among FDRs of PC probands with non-O blood than among FDRs of probands with type O. PC risk is higher among parents of probands with non-O blood, and female FDRs and mothers of probands with non-O blood. Possible clustering of non-O blood type in families may contribute to increased PC risk. Citation Format: Aarti Kolluri, Samuel O. Antwi, Sarah E. Fagan, Kari G. Chaffee, Brendan T. Broderick, William R. Bamlet, Ann L. Oberg, Robert R. McWilliams, Gloria M. Petersen. Risk of pancreatic cancer is increased among first-degree relatives of pancreatic cancer probands who have non-O ABO blood type [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1239.

AbstractBackground: Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly penetrant familial melanoma and pancreatic cancer in non-Hispanic whites (NHW). To date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on the risk of pancreatic cancer among minority subjects.Methods: We sequenced CDKN2A in 220 African American (AA) pancreatic cancer cases, 900 noncancer AA controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 NHW patients with pancreatic cancer. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for both a case–case comparison of RCV frequencies in AAs versus NHWs, and case–control comparison between AA cases versus noncancer AA controls plus Nigerian controls. Smaller sets of Hispanic and Native American cases and controls also were sequenced.Results: One novel missense RCV and one novel frameshift RCV were found among AA patients: 400G>A and 258_278del. RCV carrier status was associated with increased risk of pancreatic cancer among AA cases (11/220; OR, 3.3; 95% CI, 1.5–7.1; P = 0.004) compared with AA and Nigerian controls (17/1,083). Further, AA cases had higher frequency of RCVs: 5.0% (OR, 13.4; 95% CI, 4.9–36.7; P < 0.001) compared with NHW cases (0.4%).Conclusions: CDKN2A RCVs are more common in AA than in NHW patients with pancreatic cancer and associated with moderately increased pancreatic cancer risk among AAs.Impact: RCVs in CDKN2A are frequent in AAs and are associated with risk for pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 27(11); 1364–70. ©2018 AACR.

Purpose Pancreatic cancer has a poor prognosis and limited treatment options. Approximately 9% of pancreatic cancers harbor a germline or somatic BRCA1 or BRCA2 ( BRCA1/2) mutation. Because poly (ADP-ribose) polymerase inhibitors have significant activity in BRCA1/2-mutant ovarian and breast cancers, RUCAPANC investigated the efficacy and safety of rucaparib in BRCA1/2-mutant pancreatic cancer. Patients and Methods RUCAPANC enrolled patients with measurable locally advanced/metastatic pancreatic cancer who had received one to two prior chemotherapy regimens. Patients received oral rucaparib (600 mg twice daily) until disease progression. The primary end point was objective response rate. Results Nineteen patients were enrolled. Sixteen of 19 BRCA1/2 mutations were germline; three were somatic. Patients had received a median of two prior chemotherapy regimens. Four patients achieved a response; two partial responses and one complete response (CR) were confirmed (objective response rate, 15.8%; 3 of 19), with an additional CR unconfirmed. The disease control rate (CR, partial response, or stable disease for ≥ 12 weeks) was 31.6% (6 of 19) in all patients and 44.4% (4 of 9) in those who had received one prior chemotherapy regimen. As prespecified in the protocol, enrollment was stopped because of an insufficient response rate among the first 15 patients. Treatment-emergent adverse events included nausea (63.2%) and anemia (47.4%). Grade ≥ 3 adverse events included anemia (31.6%), fatigue (15.8%), and ascites (15.8%). Secondary resistance mutations were detected in circulating free tumor DNA in two patients with a germline BRCA2 mutation. These mutations are predicted to lead to the reversion of a somatic—not germline—mutation. Conclusion Rucaparib provided clinical benefit to patients with advanced pancreatic cancer and a BRCA1/2 mutation, and demonstrated an acceptable safety profile. Additional trials of rucaparib in this population are warranted.

Introduction: Optimal scheduling and calendar management in an outpatient chemotherapy unit is a complex process that is driven by a need to focus on safety while accommodating a high degree of variability. Primary constraints are infusion times, staffing resources, chair availability, and unit hours. Methods: We undertook a process to analyze our existing management models across multiple practice settings in our health care system, then developed a model to optimize safety and efficiency. The model was tested in one of the community chemotherapy units. We assessed staffing violations as measured by nurse-to-patient ratios throughout the workday and at key points during treatment. Staffing violations were tracked before and after the implementation of the new model. Results: The new model reduced staffing violations by nearly 50% and required fewer chairs to treat the same number of patients for the selected clinic day. Actual implementation results indicated that the new model leveled the distribution of patients across the workday with an 18% reduction in maximum chair utilization and a 27% reduction in staffing violations. Subsequently, a positive impact on peak pharmacy workload reduced delays by as much as 35 minutes. Nursing staff satisfaction with the new model was positive. Conclusion: We conclude that the proposed optimization approach with regard to nursing resource assignment and workload balance throughout a day effectively improves patient service quality and staff satisfaction.

BACKGROUNDDespite the success of immune checkpoint and targeted therapy, many patients with melanoma ultimately require further treatment. The combination of carboplatin, paclitaxel, and bevacizumab (CPB) has demonstrated promising activity in a single‐arm study. In the current study, the authors performed a randomized phase 2 study to confirm efficacy and to determine whether adding everolimus would increase the activity of the combination.METHODSThrough the North Central Cancer Treatment Group, a total of 149 patients with unresectable AJCC 6th edition stage IV melanoma were randomized from May 2010 to May 2014 to either CPB or CPB with everolimus (CPBE). The primary endpoint was progression‐free survival (PFS), with secondary endpoints of overall survival (OS), response rate, and tolerability.RESULTSThe CPB and CPBE treatment arms were balanced with regard to age (median age: 59 years vs 58 years) and high lactate dehydrogenase (48% vs 51%), but were unbalanced with regard to sex (male sex: 72% vs 55%; P = .03). Overall, there was no difference noted with regard to PFS, with a median PFS of 5.6 months for CPB versus 5.1 months for CPBE (hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 0.81‐1.62 [P = .44]), or for OS, with a median OS of 14.5 months for CPB versus 10.8 months for CPBE (HR, 1.16; 95% CI, 0.84‐1.84). The confirmed response rate was 13% for CPB and 23% for CPBE (P = .13). Toxicity was higher for CPBE compared with CPB (83% for grade 3 + and 14% for grade 4 + vs 63% for grade 3 + and 11% for grade 4+, respectively) (toxicities were graded using the Cancer Therapy Evaluation Program of the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Common grade 3 + toxicities were neutropenia, leukopenia, and fatigue, which occurred in both treatment arms with comparable frequency.CONCLUSIONSBoth experimental arms demonstrated activity, with a PFS of >5 months. However, the addition of everolimus to CPB failed to improve outcomes, with increased toxicity noted. These findings replicate the moderate antitumor activity of CPB, with future development possibly in combination with targeted or immunotherapy. Cancer 2018;124:537‐45. © 2017 American Cancer Society.

Abstract Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that normally inhibits immune responses when appropriate. In the setting of cancer, IDO pathway-mediated immune suppression is exploited by tumors in order to prevent and defeat anti-tumor immunity. Small-molecule inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. Additionally, pre-clinical tumor models have shown complementary effects with indoximod / anti-PD1 checkpoint inhibitor treatment combinations. A clinical trial was developed based upon these data. Methods: Upon successful completion of a Phase 1b dose escalation cohort, metastatic melanoma patients were enrolled in a single arm Phase 2 trial evaluating the addition of indoximod to standard of care checkpoint inhibitors approved for melanoma. Treating physicians were allowed to administer their choice of approved checkpoint inhibitor. The large majority of patients received indoximod with pembrolizumab and this interim report is limited to those patients. Indoximod was administered continuously in 21 days cycles (1200mg po twice daily) concurrently with pembrolizumab (3mg/kg q21 days). Study endpoint is best overall response (objective response rate (ORR) = complete response rate (CR) + partial response rate (PR)) per site reported RECIST criteria. Results: At time of data cut-off, 60 patients had received indoximod /pembrolizumab and were evaluable for response, defined as having at least one follow-up imaging study performed. The ORR was 52% (31/60) with a CRR of 8% (5/60). The combination was well tolerated. The most frequently reported adverse events (regardless of attribution), occurring in ≥ 20% of subjects, were fatigue, diarrhea, nausea, arthralgia, headache, cough, rash, pruritus, and hypertension. The most frequently reported laboratory abnormalities (regardless of attribution), were anemia (17%) and hyperglycemia (17%). Conclusions: The interim analysis of the combination of indoximod and pembrolizumab demonstrates an ORR of 52% which compares favorably with the established ORR for pembrolizumab alone. Updated data to be presented. NCT02073123. Citation Format: Yousef Zakharia, Robert McWilliams, Monaster Shaheen, Kenneth Grossman, Joseph Drabick, Mohammed Milhem, Olivier Rixie, Samir Khleif, Ryan Lott, Eugene Kennedy, David Munn, Nicholas Vahanian, Charles Link. Interim analysis of the Phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT117. doi:10.1158/1538-7445.AM2017-CT117