Chaffee, Kari G.

Genetic research generates results with implications for relatives. Recommendations addressing relatives’ access to a participant’s genetic research findings include eliciting participant preferences about access and choosing a representative to make decisions about access upon participant incapacity/death. Representatives are likely to be blood relatives or spouse/partners (who may share genetically related children). This raises the question of whether relatives hold similar attitudes about access or divergent attitudes that may yield conflict. We surveyed pancreatic cancer biobank participants (probands) and relatives in a family registry (blood relatives and spouse/partners of probands); 1,903 (>55%) surveys were returned. Results revealed few attitudinal differences between the groups. A slightly higher proportion of blood relatives agreed with statements reflecting proband privacy. In conclusion, probands’ decisions on access are likely to be accepted by relatives; in choosing a representative, probands may not face major differences in attitudes about privacy/sharing between a blood relative and a spouse/partner.

Key Points PRS, based on the known CLL loci, predicts CLL risk with high discrimination. This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

AbstractThe prevalence of liver dysfunction and its association with outcomes in patients with previously untreated chronic lymphocytic leukemia (CLL) is unknown. Newly diagnosed (<12 months) previously untreated CLL patients seen at Mayo Clinic, Rochester, MN between 9/1993 and 4/2016 who had baseline assessment of at least one liver function test (LFT) were included in this analysis. The prevalence of liver dysfunction at baseline, proportion of patients who acquired LFT abnormalities, time to first therapy (TTFT) and overall survival (OS) were assessed. An abnormal LFT was present in 82/2336 (3.5%) patients at diagnosis and was associated with advanced Rai stage (Rai III–IV) (21% vs. 6%; P < .001), lower hemoglobin (13.1 g/dL vs. 13.9 g/dL; P < .001), and lower platelet count (187 × 109/L vs. 200 × 109/L; P = .03). Additionally, 236 patients with normal LFTs at diagnosis developed acquired liver dysfunction during follow‐up. Patients with abnormal LFTs at diagnosis had a shorter OS compared to those with normal LFTs (HR 1.80 95% CI 1.13‐2.87; P = .014, adjusted for age, sex, Rai stage, and treatment), although TTFT was not different. Of 52 patients who underwent a liver biopsy, CLL was present in liver tissue in 39/52 (73%) patients, with the portal tracts the most common region involved. Histopathology findings of liver involvement by CLL had limited correlation with choice of CLL therapy. In conclusion, approximately 1 of 25 newly diagnosed CLL patients has abnormal LFTs at diagnosis. Although the TTFT was not different among patients with abnormal LFTs, these patients have a shorter OS compared to those with normal LFTs.

THBS2 and CA19-9 markers in human blood improve detection of pancreatic ductal adenocarcinoma.

Abstract Background: There have been varying reports on risk of different cancers, other than pancreatic cancer (PC), among first-degree relatives (FDRs) of PC patients. Because the pattern and scope of aggregation of PC with other malignancies in families of PC patients are not entirely clear, we investigated risk of 15 common malignancies among FDRs of unselected PC probands. Methods: The study included 17,181 FDRs with more than 336,000 person-years at risk. The FDRs were identified through sequentially enrolled PC probands (n=2,305) in the Mayo Clinic prospective pancreatic cancer patient registry from 2000-2016. Data on family history of cancer were provided by the probands at the time of enrollment in structured risk factor questionnaires. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing cases of each cancer type observed among the FDRs with those expected using data from the Surveillance Epidemiology and End Results Program (SEER). Stratified analyses were performed among siblings of the probands based on whether the related proband tested positive for a mutation in ATM, BARD1, BRCA1, BRCA2, CDKN2A, CHEK2, MUTYH, NBN, PALB2, or PMS2; or tested negative for mutation in a total of 25 sequenced cancer susceptibility genes. Results: Compared to the SEER reference population, risk of PC was two-fold higher than expected among the FDRs (SIR=2.04, 95% CI: 1.78-2.31) and 12-fold higher than expected among FDRs with history of PC in at least two blood relatives (SIR=11.99, 95% CI: 10.48-13.64). Siblings of mutation-positive probands had higher risk of PC (SIR=13.57, 95% CI: 6.19-25.76) than siblings of mutation-negative probands (SIR=8.91, 95% CI=6.73-11.57). For other cancer types, primary liver cancer was elevated among female FDRs (SIR=2.10, 95% CI: 1.34-3.12), whereas breast (SIR=3.16, 95% CI: 1.63-5.52) and ovarian (SIR =6.61, 95% CI: 1.33-19.31) cancers were elevated only among siblings of the mutation-positive probands. There also were suggestions of lower than expected risk of other malignancies, such as bladder, colorectal and prostate cancers, among the FDRs as compared with the SEER population. Conclusions: These findings confirm familial aggregation of PC with breast and ovarian cancers, and further suggest a potential aggregation of PC and primary liver cancer among female FDRs of PC probands. The elevated risks of breast cancer and ovarian cancer among siblings of the mutation-positive probands suggests a strong influence of genetic susceptibility shared with the related proband, possibly due to an inherited mutation in BRCA1, BRCA2, or PALB2. These findings lend support to genetic counseling and targeted screening of certain cancers in high-risk families. Citation Format: Samuel O. Antwi, Sarah E. Fagan, Kari G. Chaffee, William R. Bamlet, McWilliams R. Robert, Ann L. Oberg, Gloria M. Petersen. Risk of different cancers among first-degree relatives of pancreatic cancer patients and impact of probands’ germline mutation on sibling cancer risk [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 4269. doi:10.1158/1538-7445.AM2017-4269