bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with referral for perioperative geriatric comanagement (GERI-CO) program in 12,398 older adults with cancer.
Authors: Shahrokni Armin , Alexander Koshy , Kim Soo Jung , McMillan Sincere , Downey Robert J. , Korc-Grodzicki Beatriz
Published: May 2020

12034

Background: At ASCO 2019, we showed that the Memorial Sloan Kettering (MSK) Geriatric Co-management (GERI-CO) program was associated with improvement in 90-day postoperative mortality rate. Now, we present factors associated with the use of such program. Methods: At MSK, patients aged 75+ can be referred for perioperative GERI-CO. We retrospectively reviewed the available data of patients aged 75+ who underwent surgery within two months of their initial visit with the surgeon (2011 to 2019). Patients that were referred for GERI-CO were compared with those who were not: sociodemographic, frailty, comorbid conditions, and surgery characteristics. Frailty level was determined using the MSK Frailty Index (score ranges from 0-11, higher scores suggest more frailty). Multivariable regression analysis was used to assess factors associated with the use of the GERI-CO Program. Results: In total 12,398 patients (4422, 35.7% GERI-CO) were included. Average time from surgical consult to geriatric visit was 9 days. Patients in the GERI-CO program were older (80.7 vs. 79.6), less likely to be non-Hispanic White (87% vs. 91%), have English as primary language (84% vs. 89%), and be fit (12% vs. 17% with MSK-FI 0). They were more likely to have stroke history (5% vs. 4%), have diabetes (DM) (25% vs.20%), hypertension (78% vs. 71%), and peripheral vascular disease (14% vs. 12%), but less likely to have cardiac disease (22% vs. 26%), myocardial infarction (MI) (7% vs. 10%), pulmonary disease (13% vs. 16%). Patients referred for GERI-CO were more likely to undergo 3+ hours surgeries (25% vs. 8%), with 100+ cc intraoperative blood loss (41% vs. 22%), and hospital length of stay (LOS) of 3+ days (42% vs. 19%). In multivariable analysis, being frail (OR = 1.3 and 1.6 for MSK-FI 1-2 and 3+), longer surgery (OR = 2.6 and 3.6 for operation time 1.5-3 and 3+ hours), longer LOS (OR = 1.3 and 1.5 for LOS 1-2 and 3+ days), older age (OR = 1.06), having DM (OR = 1.15) were associated with higher likelihood of GERI-CO while having history of cardiac disease (OR = 0.55), MI (OR = 0.84), pulmonary disease (OR = 0.69) were associated with less likelihood of referral for GERI-CO. Conclusions: Our result shows the unique characteristics of patients managed in the GERI-CO program. This has implications for both implementation of GERI-CO program in other institutions and assessing outcomes of these patients.
Patient controlled analgesia (PCA) vs non-PCA intravenous hydromorphone titration for severe cancer pain: A multi-center, phase III trial, HMORCT09-1.
Authors: Lin Rongbo , Lin Sunzhi , Zhu Jinfeng , Feng Shuitu , Wu Qingyi , Fu Jianqian , Wang Fang , Li Hui , Li Xiaofeng , Zhang Gaowang , Yao Yongzhi , Xin Min , Lai Tianyang , Lv Xia , Chen Yigui , Lin Yubiao , Hong Lixia , Lin Shaowei , Zhao Shen , Huang Cheng
Published: May 2020

12078

Background: The titration of opioid dosage is necessary for adequate pain relief with acceptable side effects among individuals with cancer pain. The titration process can be achieved by non-patient administration or PCA pump. The aim of this study was to evaluate the efficacy of PCA versus non-PAC titration for severe cancer pain. Methods: Patients with severe cancer pain (NRS ≥ 7/10 at rest) were randomized into PCA or non-PCA titration and stratified by opioid tolerance or intolerance. For PCA, the pump was set as no continuous dose, hydromorphone bolus dose was 10%-20% of the total equianalgesic of past 24h for opioid tolerance, or 0.5 mg for opioid intolerance. The lockout time was 15 min. For non-PCA, initial hydromorphone bolus was the same with PCA. Reassess pain at 15 min. The dose of hydromorphone was increased by 50%-100% if pain unchanged or increased, or repeated if NRS was 4-6, or continue at current dose as needed if NRS≤3. The primary endpoint was the time to successful titration (TST) - time from start to the time of pain controlled at NRS ≤ 3 in two consecutive evaluation with 15-min intervals, which was tested by K-M curve. Results: A total of 214 patients were randomized (106 in PCA, 108 in non-PCA) in 17 study sites. The most common sites of primary cancer were lung (21.03%), stomach (15.89%), colorectal (14.49%) etc. Median TSTs were 0.50h in PCA, 0.79h in non-PCA, HR 1.64 (95% CI 1.23, 2.17, P = 0.00127). In opioid tolerance, 0.50h in PCA, 1.00h in non-PCA (HR 1.92, 95% CI 1.32, 2.78, P = 0.0025). while in opioid intolerance, 0.50h in PCA and 0.50 in non-PCA (HR 1.35, 95% CI 0.88, 2.04, P = 0.162). The median dosage of hydromorphone for TST was 1.00mg (P25, P75 0.50, 2.00) in PCA, 1.50mg (P25, P75 1.00, 2.50) in non-PCA (P = 0.086). In opioid tolerance, 1.00mg (P25, P75 1.00, 2.00) in PCA, 2.00mg (P25, P75 1.00, 4.00) in non-PCA (P = 0.009). In opioid intolerance, 1.00mg (P25, P75 0.50, 2.00) in PCA and 1.00 mg (P25, P75 0.50, 2.00) non-PCA (P = 0.793). Mean patient satisfaction assessed by ESAS score was significantly superior in PCA to non-PCA (0.62±0.67 vs 1.27±0.98 for ITT, 0.66±0.66 vs 1.39±1.00 for opioid tolerance, and 0.56±0.69 vs 1.13±0.95 for opioid intolerance). Adverse events were similar in both PCA/non-PCA groups. Conclusions: PCA IV hydromorphone titration provided quicker analgesic effect, higher patients satisfaction, and a similar tolerability as compared to non-PCA administration in patients with severe cancer pain. Clinical trial information: NCT03375515 .
Value of oncologist generated “surprise question” in predicting survival in metastatic cancer.
Authors: Edge Stephen B. , Liu Lu , Case Amy Allen , O'Connor Tracey L. , Kuvshinoff Boris W. , Murphy Monica L. , McKinney Mishellene
Published: May 2020

12082

Background: Treating patients with metastatic cancer (MCA) requires timely integration of palliative and hospice care (PHC). The Surprise Question (SQ-“Would you be surprised if your patient died in the next year?”) may help predict short-term mortality in patients with chronic disease and prompt initiation of PHC. There limited data on the utility of the SQ in oncology and none controlling for age and cancer site (CS). This study evaluates the SQ in MCA. Methods: SQ data were collected using a clinical oncology pathway program (COP) in which the treating oncologist is required to answer the SQ for all patients with MCA. The cohort includes MCA patients with SQ entries from 5-1-2018 to 4-30-2019 providing cohorts with 6- and 12-months follow-up (f/u) from the date of the SQ. Vital status was determined as of 1-15-20. Over 90% of deaths are reported with 3 months of death. Models using SQ response (yes/no), cancer site and age were tested with logistic regression (LR) with Akaike Information Criterion (AIC) for model selection (lower number best model) and ANOVA to assess the value of the SQ in predicting mortality. Results: There were 655 and 1276 patients with MCA in COP with 1 year and 6 months f/u from the SQ, respectively. The proportion with the SQ response “No” (shorter expected survival) varied by cancer site (range 19% – 82% - e.g. breast 42%; pancreas 81%). The SQ was the best predictor compared to cancer site and age for 6 and 12-month mortality (LR Model A – lowest AIC). The odds ratio of death at one year from SQ-No vs. SQ-Yes was 3.8 (95% CI 2.7, 5.4) with a strong association between SQ response and 1-year and 6-month mortality (p < 0.001). See Table. Conclusions: Oncologist assessment of survival expectancy by the SQ in MCA is a strong predictor of mortality beyond cancer site and age. The treating oncologist’s response to SQ can serve as a simple and reliable predictive tool to identify those with MCA likely to die sooner who may benefit from timely referral to PHC. [Table: see text]
Efficacy and safety of direct oral anticoagulants (DOACs) and low molecular weight heparin (LMWH) for primary prevention of venous thromboembolism (VTE) in ambulatory cancer patients.
Authors: Shenouda Mina , Desai Ruchi , Jaglal Michael Vishal
Published: May 2020

12088

Background: Active malignancy is a well described risk factor for thrombosis. Randomized clinical trials (RCT) have evaluated anticoagulation (AC) with DOACs or LMWH for prevention of VTE in ambulatory cancer patients. This objective of this meta-analysis is to evaluate the efficacy and safety of DOACs and LMWH thromboprophylaxis in adult patients with active solid organ malignancy or lymphoma. Methods: We conducted a search of MEDLINE, EMBASE, and CENTRAL from 10/31/2009-11/31/2019. Data for meta-analysis was extracted from studies that met inclusion criteria (RCT, ambulatory patients age >18 years with active solid organ malignancy or lymphoma, prophylactic AC with DOAC or LMWH). Risk ratio (RR) were calculated for primary (efficacy) end point of VTE occurrence and secondary (safety) end points of major bleeding (MB) and clinically relevant non-major (CRNMB). Subgroup analyses of efficacy and safety endpoints were conducted based on AC and cancer types. Results: Eleven trials met inclusion criteria with total of 7741 participants. Two trials evaluated DOACs and nine trials evaluated LWMH for thromboprophylaxis. Efficacy results are noted in Table. Safety outcomes for MB and CRNMB for AC were RR 1.83 (95% CI 1.26, 2.65), p=0.001 and RR 1.36 (95% CI 1.05, 1.76), p=0.02. Safety outcomes for MB and CRNMB for DOAC were RR 1.95 (95% CI 0.88, 4.30), p=0.10 and RR 1.35 (95% CI 0.80, 2.27), p=0.26. Safety outcomes for MB and CRNMB for LMWH were RR 2.05 (95% CI 1.19, 3.51), p=0.009 and RR 1.44 (95% CI 1.01, 2.05), p=0.04. Conclusions: Both DOACs and LMWH decrease risk for VTE development in ambulatory adult cancer patients. MB and CRNMB were significantly increased in patients taking LMWH but not in patients taking DOACs. A large clinical trial using DOACs for thromboprophylaxis would help elucidate the thrombosis and bleeding event rate in ambulatory cancer patients. [Table: see text]
Inflammatory and clinical risk factors for chemotherapy-induced peripheral neuropathy (CIPN): A nationwide longitudinal study in 143 cancer patients during chemotherapy.
Authors: Kleckner Ian , Jusko Todd , Culakova Eva , Kleckner Amber , Asare Matthew , Inglis Julia Ellen , Loh Kah Poh , Peppone Luke Joseph , Berenberg Jeffrey L. , Conlin Alison Katherine , Ossip Deborah J. , Mustian Karen Michelle
Published: May 2020

12099

Background: CIPN is a common dose-limiting side effect of taxane and platinum chemotherapy. It is difficult for clinicians to predict who will experience CIPN before initiating chemotherapy, partly because the etiology of CIPN is poorly understood. Specifically, although inflammation putatively plays a role in CIPN, there is limited evidence of the role of inflammation in CIPN in humans. Here, we identified the strongest predictors of CIPN using variables measured before taxane or platinum chemotherapy, including serum inflammation. Methods: 143 sedentary patients with cancer (81% breast, 7% colon, 5% lung; 7% other; mean age 56 years) receiving taxane or platinum chemotherapy rated the severity of (a) numbness and tingling, and (b) hot/coldness in hands/feet on 0-10 point scales before and after their first 6 weeks of chemotherapy. Linear regression models were fit to predict CIPN symptom severity at 6 weeks using variables related to inflammation (serum IL-1β, IL-6, IL-8, IL-10, IFN-γ, sTNFR1; 69 patients who gave blood), clinical factors (cancer stage, baseline neuropathy, fatigue, anxiety, depression, using diabetes medications), behavior (daily pedometer steps), and demographics (age, race) measured before chemotherapy. The final model was identified by the smallest AIC goodness of fit. Results: The strongest pre-chemotherapy predictors of numbness and tingling after 6 weeks of taxane and/or platinum chemotherapy were worse patient-reported fatigue/anxiety/depression (explaining 25% of variance), platinum chemotherapy (7%), and older age (5%). The strongest predictors of hot/coldness in hands/feet included worse baseline neuropathy (13%), platinum chemotherapy (8%), and fatigue/anxiety/depression (6%). In the 69 patients with serum data, a more pro-inflammatory state was a risk factor for CIPN as higher levels of pro-inflammatory IL-1β (7%) predicted numbness/tingling, and lower levels of anti-inflammatory IL-10 (7%) predicted hot/coldness in hands/feet. Conclusions: The strongest pre-chemotherapy predictors of CIPN included worse fatigue/anxiety/depression and platinum chemotherapy in this sedentary population of cancer patients (mostly breast). A pro-inflammatory state before chemotherapy may also increase risk for CIPN, suggesting that inflammation may underlie the etiology of CIPN in humans. Clinicians should consider assessing these factors to inform the patient’s risk for CIPN. Funding: NCI UG1CA189961, NCI K07 K07CA221931, T32CA102618. Clinical trial information: NCT00924651 .
Impact of embedded palliative care providers compared to externally available palliative care services on the number of patients receiving palliative care referrals in a large community oncology practice.
Authors: Young Garrett , Lyss Aaron J. , Blakely Johnetta , Owens Leah , Dickson Natalie R. , Schleicher Stephen Matthew
Published: May 2020

12103

Background: Palliative care improves quality of life and may increase overall survival in patients with solid tumor malignancies. Despite having the ability to refer patients to in-home and external palliative care services, we observed low palliative care referral rates in our practice of 90 oncologists across 30 clinics. We tested whether embedding palliative care providers directly in clinic would improve palliative care referral rates for solid tumor patients. Methods: Between 2017 and 2020, we embedded an independent palliative care provider into five clinics across middle Tennessee. Access to external palliative care services was present both before and after the intervention. Using data from our EHR and billing systems, we performed a pre-post analysis measuring palliative care referrals in the six-month periods immediately before (pre-intervention period) and after (post-intervention period) a palliative care provider was embedded in each clinic. Statistical significance was assessed using Welch’s two sample t-test. Results: 8,636 unique solid tumor patients were seen in the five clinics during the study periods (Table). Despite having the ability to refer patients to external palliative care services in the pre-intervention period, the placement of a palliative care provider into clinic increased the number of solid tumor patients that received a palliative care referral per month at all clinics (min.: 200%; max.: 990%; median: 600%). Four of the five increases were statistically significant (p-values < 0.05). Conclusions: Even when external palliative care services are available, embedding palliative care providers into community oncology clinics significantly increases the rate of palliative care referrals for solid tumor patients. [Table: see text]
A highly effective and practical desensitization regimen: Results in comparable clinical outcomes for multiple myeloma patients with skin rash after immunomodulatory drugs.
Authors: Firoozmand Amin , Ali Naveed , Ahmed Nausheen , Fu Pingfu , Cao Shufen , Brown George , Schmikla Hannah , Driscoll James Joseph , O' Brien Timothy , Caimi Paolo Fabrizio , De Lima Marcos J.G. , Malek Ehsan
Published: May 2020

12104

Background: Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy for patients with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% in some reports impeding maximal benefit of this agent. The optimal management of IMiDs-associated skin is unclear. The concurrent weekly Dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD. Furthermore, we assessed the impact of this desensitization regimen on clinical outcome. Methods: A total of 160 patients were evaluated. The incidence of rash was found to be 13% (n = 21). A cohort of age- and gender-matched without rash (n = 39) was randomly selected. The effects of rash on overall and progression free survival (OS and PFS) were further estimated using Cox regression controlling the effects of age and gender. Results: Median time to development of rash after IMiD initiation was 28 days (range, 2-232). Rashes were graded as low (I-II) in 89% (n = 17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all patients were able to restart the same IMiD with none re-experiencing any dermatologic adverse effect afterward. Comparing to no-rash controls, there was no significant difference in PFS (0.13) or OS (p = 0.12) in multivariate regression model. Conclusions: Proposed 3-week corticosteroid regimen showed 100% success rate in reinstituting IMiDs in our cohort. It may provide a highly effective and practical short term immunosuppression required to enable patients to restart IMiDs and enjoy comparable outcome to pts without skin rash.
Health and cancer concerns among siblings of childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Morales Sonia , Mirzaei Salehabadi Sedigheh , Srivastava Deokumar , Gibson Todd M. , Leisenring Wendy M. , Lown Anne , Zeltzer Lonnie K. , Armstrong Gregory T. , Krull Kevin R. , Buchbinder David Kyle
Published: May 2020

12117

Background: Siblings of long-term survivors of childhood cancer can be at risk for persistent concerns regarding their future health and risk for cancer. We examined self-perceived future health and cancer risk concerns among such siblings. Methods: 3,969 siblings (median age 29 [range 18–56] years) of 5+ year matched pair cancer survivors (n= 3,969; age 25 [6–48] years; time since diagnosis 19.6 [9.6-33.8] years) in the CCSS self-reported physical/psychosocial problems, including concerns regarding future health and cancer risk (dichotomized as concerned vs not concerned). Chronic health conditions (CHC) were graded using the Common Terminology Criteria for Adverse Events system: mild (grade 1), moderate (grade 2), severe/disabling (grade 3),or life-threatening (grade 4). Sibling demographics, their matched survivor’s diagnosis, era and treatment components, complications (death, relapse, disfigurement) as well as self-reported health status and CHCs for siblings and survivors were examined as potential risk factors for concern using multivariable logistic regression. Adjusted odds ratios (OR) and 95% confidence intervals (CI) are reported. Results: The prevalence of siblings reporting concerns regarding health and cancer risk decreased based on decades of matched survivor diagnosis: 1970-79 (73.3%; 63.9%), 1980-89 (67.2%; 62.6%), 1990-99 (45.7%; 52.3%). Risk factors for concerns included sibling poor/fair current health (future health OR 3.65, 95% CI 2.37-5.62; cancer risk OR 1.54, 1.12-2.13) compared to good/very good/excellent health. Sibling grade 2 (future health OR 1.46, 1.23-1.74; cancer risk OR 1.20, 1.01-1.42) or grade 3-4 CHCs (future health OR 1.37, 1.09-1.71; cancer risk OR 1.28, 1.03-1.58) were associated with greater concerns compared to those with less than grade 2 CHCs. Survivor treatment with chemotherapy/radiation was associated with elevated cancer risk concerns (OR 1.51, 1.13-2.02) compared to surgery/no therapy. Siblings of survivors with grade 3-4 CHCs (OR 1.35, 1.12-1.63) had greater future health concerns compared to those with less than grade 2 CHCs. Sibling bereavement was a risk factor for future health (OR 1.45, 1.04-2.03) and cancer risk (OR 1.44, 1.05-1.99) concerns. Conclusions: The prevalence of sibling concerns regarding future health and cancer have diminished in more recent decades. Subgroups of siblings are at-risk for concerns over future health and cancer risk, partially determined by medical characteristics of their survivor and their own health status.
Vitamin D supplements and marine omega-3 fatty acids and development of advanced cancer.
Authors: Chandler Paulette , Chen Wendy Y. , Ajala Oluremi , Hazra Aditi , Cook Nancy , Bubes Vadim , Lee I-Min , Giovannucci Edward L. , Buring Julie , Manson JoAnn E ,   VITAL Research Group
Published: May 2020

1510

Background: Epidemiologic data suggest that vitamin D supplementation may reduce cancer mortality. We tested whether vitamin D and/or omega-3 supplementation reduces the incidence of advanced stage cancer at diagnosis or lethal cancer, and whether body mass index (BMI) modifies these associations. Methods: The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, placebo-controlled, 2x2 factorial trial of vitamin D3 (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acids (1 g/day) that enrolled men aged ≥50 years and women aged ≥55 years free of cancer and cardiovascular disease at baseline. For this particular analysis, the primary outcome is a composite of metastatic and fatal invasive total cancer. Secondary analyses included examination of BMI (<25, 25-<30, and >= 30 kg/m2) as effect modifiers of the observed associations. Results: VITAL randomized 25,871 participants, among whom 1,617 were diagnosed with invasive cancer over a median 5.3 year intervention period. No significant differences by treatment arm (vitamin D vs placebo: hazard ratio [HR]=0.96; 95% confidence interval, 0.88-1.06; p=0.47; omega-3 vs placebo; HR 1.03 [0.93-1.13]; p=0.56) were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D, compared to placebo (226 assigned to vitamin D and 274 to placebo; HR 0.83 [0.69-0.99]; p=0.036). There was no difference by omega-3 assignment (246 assigned to omega-3 and 254 to placebo: HR 0.97 [0.81-1.15], p=0.72). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI<25: HR 0.62 [0.45-0.86], but not among those who were overweight or obese (BMI 25-<30: HR 0.89 [0.68-1.17]; BMI >=30: HR 1.05 [0.74-1.49]); p for interaction by BMI =0.03. There was no effect modification by BMI noted for the omega 3 arm. Conclusions: In a randomized clinical trial, supplementation with vitamin D, but not omega-3s, reduced incidence of advanced (metastatic or fatal) cancer in the overall cohort, with strongest risk reduction in normal weight individuals. Further research is needed to understand these findings. Clinical trial information: NCT01169259.
The impact of poly ADP ribose polymerase (PARP) inhibitors on clonal hematopoiesis.
Authors: Bolton Kelly L , Moukarzel Lea Anne , Ptashkin Ryan , Gao Teng , Patel Minal , Caltabellotta Nicole , Braunstein Lior Zvi , Aghajanian Carol , Hyman David Michael , Berger Michael F. , Diaz Luis A. , Li Bob T. , Abida Wassim , Schram Alison M. , Weigelt Britta , Friedman Claire Frances , Zehir Ahmet , Papaemmanuil Elli , Cadoo Karen Anne , Levine Ross L.
Published: May 2020

1513

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors are an important new class of anti-cancer therapies. Therapy-related myeloid neoplasia (tMN) has been reported following PARPi therapy, and is associated with adverse outcomes. Further insight is required into the risk of tMN conferred by PARPi therapy, independent of germline genetic background and prior therapy. We have shown that oncologic therapy selects for acquired mutations in the blood (clonal hematopoiesis; CH) particularly those in the DNA damage response pathway (DDR) including PPM1D, TP53 and CHEK2 and that CH confers an increased risk of tMN. We hypothesized that characterization of the relationship between CH and PARPi therapy provides insight into its potential for leukemogenesis and may offer opportunities for tMN prevention. Methods: We assessed for CH in the blood of 10,156 cancer patients, including 54 who received PARPi therapy, 5942 who received another systematic therapy or radiation therapy and 4160 untreated prior to blood draw. Results: Patients exposed to PARPi therapy were more likely to have CH (33%) compared to those exposed to other systemic therapies or radiation (18%) or untreated patients (16%). This was particularly pronounced for DDR CH; 25% of PARPi treated patients had DDR CH compared to 2% of untreated patients. In a multivariable model accounting for demographics, exposure to chemotherapeutic agents, radiation therapy and germline BRCA mutation status, exposure to PARPi conferred an increased risk of DDR CH (OR = 3.6, 95% CI 1.5-8.5, p = 0.004). This effect was attenuated after accounting for cumulative exposure to therapy (OR = 2.8, 95% CI 0.97-8.2, p = 0.06) suggesting a multifactorial contribution to the enrichment of CH following PARPi therapy. To characterize this further we performed a prospective collection of patients with CH over a median follow-up time of 58 months. During the follow-up period, 17 patients received PARPi, 360 received cytotoxic therapies or radiation and 232 were untreated or received targeted therapies. The growth rate of DDR CH was significantly higher among those who were exposed to PARPi (median, +2.8% increase in VAF per year) compared to untreated patients (+0.08% per year, p = 0.02) and those exposed to other cytotoxic therapies (+1% per year, p = 0.04). Conclusions: Taken together our data suggests that PARPi therapy promotes the expansion of DDR CH. Future studies should examine the potential of CH to identify individuals at high risk of tMN following PARPi therapy and to develop therapies aimed to prevent tMN in patients with CH.
Clinical conundrums: Developing a strategy for discerning TP53-associated chip and coherent clinical care.
Authors: Weitzel Jeffrey N. , Garber Judy Ellen , Castillo Danielle , Sand Sharon , Mejia Rosa , Cervantes Aleck , Stokes Samantha , Mokhnatkin Janet , Tsang Kar Wing Kevin , Wang Jinhui , Wu Xiwei , Herzog Josef , Nehoray Bita , Slavin Thomas Paul
Published: May 2020

1514

Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). However, approximately 20% of commercial laboratory multigene panel test (MGPT)-detected pathogenic TP53 variants represent aberrant clonal expansion (ACE), rather than a germline finding, and are often detected in individuals that lack classic features of LFS. Clonal hematopoiesis (CH) is a form of ACE, and in the absence of an abnormal hemogram is termed Clonal hematopoiesis of indeterminate potential (CHIP). CHIP is often associated with a pathogenic variant (PV) in hematopoietic pathway gene(s) at a variant allele frequency (VAF) less than expected for a heterozygous germline finding. The prevalence increases with age and exposure to chemotherapy. The presence of a skewed VAF is usually noted in a comment on a genetic test result, however, clinicians without genetic training often lack understanding of the comment and need strategies to discern the difference between germline findings, CHIP, and post-zygotic mosaicism. Our studies illuminate possible strategies for discernment for clinicians. Methods: Among 113 cases with MGPT-detected TP53 PVs, enrolled in the Clinical Cancer Genomics Community Research Network registry, we obtained additional tissues, family history and complete blood count (CBC) reports on 42 cases. DNA extracted from formalin fixed paraffin embedded (FFPE) tumor/normal tissues, blood, saliva, eyebrow plucks, was analyzed using a previously validated custom myeloid and CH gene (n = 79) amplicon-based QIAseq panel. PVs with VAF > 2% were included in analyses. Results: Germline status was confirmed for 6 cases (one with a CH PV), post-zygotic mosaicism was supported for 5 cases and 2 were indeterminant. 12 had results supporting ACE/CH, with additional CH-associated PV(s) identified in 5/12 (41%); n = 2 of each TET2, ATM, TP53; and increasing VAF over time for the driver TP53 PV was noted in 2. Of these 2 one was identified to have a hematopoietic malignancy identified through analysis of the CBCs and bone marrow biopsy in parallel with the increasing VAF. Additional results are pending for 7 cases. Conclusions: With the use of our multi-tissue NGS strategy, serial sampling of suspected ACE/CH cases, family history and CBC analyses we were able to discern the status of most TP53 genetic findings. This work has direct translational impact, refining risk estimation and improving the clinical care of patients with TP53 PVs, while avoiding unnecessary LFS-related care and enabling appropriate care for those with ACE.
Evaluation of a mainstream model of genetic testing for men with prostate cancer.
Authors: Scheinberg Tahlia , Goodwin Annabel , Ip Emilia , Linton Anthony , Mak Blossom , Smith David P , Stockler Martin R. , Strach Madeleine Cornelia , Tran Ben , Young Alison Luk , Zhang Alison Yan , Mahon Kate Lynette , Horvath Lisa
Published: May 2020

1521

Background: In order to identify the ∼12% with inherited cancer predisposition, it is recommended that all men with metastatic prostate cancer (mPC) be offered testing. This has implications for treatment choices and cancer prevention in family. Limited geneticists/genetic counsellors globally present a major barrier to testing. We tested a potential solution, mainstreaming, where testing is performed by the patient’s oncologist. Methods: Men with mPC at three Australian sites were offered germline genetic testing at their medical oncology appointment. Panel testing ( ATM, BRCA1, BRCA2, BRIP1, CHEK2, EPCAM, FANCA, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D and TP53) was performed on saliva/blood (Invitae). Primary outcomes were clinician and patient acceptability (modified Royal Marsden Satisfaction Questionnaires). Secondary outcomes included mutation rates and cost-effectiveness. A sample size of 44 provided 90% power, with a one-sided alpha of 5%, to distinguish a proportion of men happy with mainstreaming of 80% vs. 60% or less. Allowing for 25% drop-out, we aimed to recruit 60 men. Results: Of 66 men offered testing from April to November 2019, 63 (95%) accepted. Four pathogenic variants were identified (2 BRCA2, 1 NBN, 1 MSH6). 48 patients and eight clinicians completed questionnaires. Acceptability was high. All (48/48) patients were happy to have been tested, and 45/48 (94%) were happy to have been tested at their oncology appointment. All were happy to receive their results from their oncologist. All clinicians were satisfied mainstreaming and 88% (7/8) felt confident doing so. Mainstreaming was cost-effective, requiring 87% fewer genetic consultations than traditional genetic counselling. Conclusions: This study shows that mainstreaming of men with mPC is feasible, resource efficient and acceptable to both clinicians and patients. Widespread implementation as a new standard of care would facilitate timely access to genetic testing for men with mPC.
Genotype and phenotype correlation of common cancer predisposition syndromes in sarcoma cases.
Authors: Zaheed Milita , Tucker Kathy , Ballinger Mandy L. , Thomas David Morgan ,   International Sarcoma Kindred Study
Published: May 2020

1524

Background: Sarcomas are rare heterogenous cancers affecting a predominantly younger population. The most recognised autosomal dominant contributor being pathogenic TP53 variants associated with Li Fraumeni Syndrome (LFS). When referred, patient eligibility for germline TP53 testing is assessed using classic or Chompret LFS criteria. Other heritable cancer syndromes which can be associated with sarcoma (breast/ovarian, colorectal) are more commonly considered in clinical practice. In some centres germline testing is offered to only those who meet established clinical criteria. Heritable cancer predisposition has several implications including therapy and clinical risk management. Here we report the concordance between clinical criteria and genotypes in sarcoma families. Methods: We included 1,664 sarcoma probands from the International Sarcoma Kindred Study. Eligibility for genetic testing was assessed using internationally accepted clinical criteria for recognised cancer syndromes. Whole genome sequencing was performed on peripheral blood DNA and variants in the ACMG cancer gene list were classified as pathogenic or likely pathogenic using established bioinformatics pipelines. Results: The median age of sarcoma diagnosis in 1664 probands (798 males, 866 Females) was 48 years (range 1-93). The median age of first cancer diagnosis was 46.5 years (0-93) with 291 probands having multiple primary cancers. Of 1504 informative pedigrees, 243 (16%) met criteria for testing; 207 (14%) TP53; 19 (1%) BRCA1/2; 2 (<1%) colorectal cancer (CRC) genes and 15 (1%) familial melanoma. Of 12 TP53 PVs identified, 9 met TP53 testing criteria. Of 13 PVs identified in HR genes (7 BRCA2, 4 PALB2 and 2 BRCA1) only 1 ( PALB2) met BRCA1/2 testing criteria and 2 met Chompret criteria. Both BRCA1 cases were male with a 1st degree relative with ovarian cancer. In CRC genes (1 APC, 2 MSH2, 4 MSH6, 1 PMS2), none met CRC testing criteria but 4 met Chompret criteria. No CDKN2A PVs were identified in melanoma families. Conclusions: In probands with sarcoma, clinical criteria for eligibility for testing for common non-LFS heritable syndromes perform poorly. This should be considered when making decisions regarding germline testing.
Effect of detection of epigenomic changes in plasma-derived cell-free DNA on multicancer classification.
Authors: Bergamaschi Anna , Haan David , Ku Jeremy , Ning Yuhong , Ellison Chris , Guler Gulfem , Phillips Tierney , McCarthy Erin , Antoine Michael , Nguyen Albert , Scott Aaron , Lloyd Paul , Ashworth Alan , Bethel Kelly , Levy Samuel
Published: May 2020

1539

Background: Epigenomic changes in DNA methylation patterns are more precisely delineated by active demethylation events as marked by 5-hydroxymethylation (5hmC) of cytosine residues. 5hmC appears to be dynamically modulated in tumor tissues and can be employed as a cancer biomarker. Strategies which interrogate 5hmC genome-wide patterns in a liquid biopsy context may provide efficient and precise technology for early cancer screening and detection. In this study we identified genome-wide 5hmC changes in plasma based circulating free DNA (cfDNA) from breast, colorectal, lung, pancreatic and prostate cancer patients versus non-cancer individuals. Methods: cfDNA was isolated from plasma, enriched for the 5hmC fraction using novel click-chemistry protocol for labelling followed by sequencing and alignment to a reference genome to construct features sets of 5hmC patterns. Regularized classification models were constructed to classify cancer samples apart from non-cancer. Results: > 500 non-cancer individuals and > 500 cancer patients across five cancer types (breast, colorectal, lung, pancreas and prostate) were included in this study. About 60% of the cancer samples were early stage disease (I or II). The ability to classify non-cancer versus cancer patients was evaluated by 5-fold cross validation of our trained prediction models. Our models were able to classify all breast cancer with a test auROC of 0.86 while prediction model classification for ER negative samples had an auROC of 0.92. Colorectal performance auROC was 0.9; lung auROC = 0.92, pancreatic auROC = 0.97 and prostate auROC = 0.91. Overall sensitivity range, when allowing 2% false positive, was between 85% and 52%. Further using 5hmC signal in blood we were able to identify several signaling pathways specifically relevant to the biology of the cancers investigated. Conclusions: These findings further demonstrate that 5hmC changes in cfDNA enable non-invasive detection of breast, colorectal, lung pancreatic, and prostate cancers. Further, 5hmC signals enabled the identification of a suite of cancer signaling pathways differentially enriched in cancers versus non-cancers. These data suggest that dynamic changes in tumor cell methylation, detectable through 5-hydroxymethylation, are contained in the circulating blood and signal active disease biology.
A sensitive and quantitative multimodal blood test for the detection of colorectal adenomas and cancer: Correlation with size and number of polyps.
Authors: Friedland Shai , Pan Jennifer Y. , Watson Drew , Chen Yu , Nimgaonkar Ashish , Gulzar Zulfiqar , Gupta Pratyush , Lucas Julian , Atkins Alex , Lai Jr-Ming , Hsieh Ben , Su Stephen , Lim Austin , Ciu Iris , Setthasap Ploy , Sninsky John J. , Mei Rui
Published: May 2020

1555

Background: Colonoscopic polypectomy is the primary reason for declining colorectal cancer incidence and mortality. Epidemiological evidence has ordered the timing and risk of pre-cancerous adenomas, localized and invasive cancer along a 7-10 year continuum. The increased size and number of index polyps are correlated with an increased probability of progression to cancer and informs surveillance colonoscopies. Methods: A single-center, IRB-approved, prospective, blinded study was conducted at the VA Palo Alto Health Care System. Results for 354 patients with no prior diagnosis of CRC who were scheduled for colonoscopy are presented. Indications for colonoscopy were 86% asymptomatic and 14% with symptoms or positive-FIT. Patients had blood drawn immediately prior to colonoscopy. The test analyzes three biomarkers: circulating gastrointestinal epithelial cells (CEC), validated somatic mutations, and methylation (SEPTIN9) of cell-free DNA and uses incident risk to calculate a CMx Score, scaled from 0 to 100. Multivariate regression methods were used to assess the degree of association between the pre-defined CMx Scores and polyp sizes and number, adjusting for both DNA mutation and DNA methylation status. Results: There is a significant association between CMx Scores and polyp size (F value = 5.80, p-value = 0.017). DNA mutation (F value = 1.29, p-value = 0.263) and methylation status (F value = 0.34, p-value = 0.560) were non-significant. Similarly, there is a significant association between CMx Scores and number of polyps (F value = 23.71, p-value < 0.0001). Again, DNA mutation (F value = 1.57, p-value = 0.210) and methylation status (F value = 1.34, p-value = 0.248) were non-significant. These results suggest that CMx Scores, which incorporate CEC, are providing predictive information of polyp sizes and number above and beyond DNA mutation and methylation status alone. Conclusions: A novel noninvasive multimodal blood-based assay that analyzes cell-free DNA for somatic mutations and methylation, CEC and integrates SEER incidence risk is significantly associated with polyp size and number. The opportunity to track progression and potentially inform colonoscopy interval is notable. [Table: see text]
Breast cancer events in women with atypical ductal hyperplasia who do not undergo surgical excision.
Authors: Kilgore Lyndsey Jo , Yi Min , Bevers Therese Bartholomew , Coyne Robin , Lazzaro Marita , Lane Deanna L , Albarracin Constance T. , Bedrosian Isabelle
Published: May 2020

1562

Background: Atypical ductal hyperplasia (ADH) found on core needle biopsy is associated with an upgrade to carcinoma in 10-30% of women, thus surgical excision remains the standard of care. We sought to review the incidence of breast cancer in women with ADH managed by either observation or surgical excision over a 15 year period. Methods: Our prospectively maintained registry was reviewed to identify patients with ADH diagnosed by core needle biopsy between 1/2004 and 10/2018. Observed patients were deemed low risk for upgrade after multidisciplinary review confirmed adequate sampling, limited atypia and concordance between imaging and histology. Surgical patients were excluded if upstaged to carcinoma following excision. Patients with < 1 year follow-up were excluded. Subsequent breast cancer was classified as ipsilateral or contralateral to the previous ADH and was further classified as index site if the new cancer was identified in the same quadrant as prior ADH. Multivariate logistic regression models were used to assess potential predictors of subsequent breast cancer events. Results: Four hundred and seventy-eight women with 483 ADH lesions met criteria; 305 were observed and 173 underwent excision. Median follow-up was 5.2 years, range 1.1-15.3. At the time of ADH diagnosis, 91 women had a personal history of breast cancer. Age < 50 was the only statistically significant difference between the groups (24.6% vs. 33.3%, p = 0.04). Race, receipt of chemoprevention, prior breast cancer history and median follow-up were not significant between the groups. Prior history of breast cancer was associated with subsequent breast cancer risk in multivariate analysis (OR 2.25, 95% CI 1.04-4.87, p = 0.04). After excluding patients with a history of breast cancer, multivariate analysis demonstrated no association of age, race, use of chemoprevention or surgical excision with future cancer risk. Among the 387 patients without a prior breast cancer history, 21 patients developed a subsequent cancer; 10 in the surgical group and 11 in the observed group (7.3% vs. 4.4% respectively, p = 0.2). Two cancers were identified at the index site in the surgery group (2/137, 1.5%) and three in those observed (3/250, 1.2%). Conclusions: Observation, rather than surgical excision, is safe in selected women that have a core biopsy diagnosis of ADH. Index site failures are rare and are superseded by cancer risk elsewhere in the breast. National screening and diagnosis recommendations should consider recommending observation for this select group of patients with ADH.
Projection of cancer incidence and death to 2040 in the US: Impact of cancer screening and a changing demographic.
Authors: Rahib Lola , Wehner Mackenzie , Matrisian Lynn McCormick , Nead Kevin Thomas
Published: May 2020

1566

Background: Coping with the current and future burden of cancer requires an in-depth understanding of cancer incidence and death trends. As of 2020, breast, lung, prostate, and colorectal cancer are the most incident cancers, while lung, colorectal, pancreas, and breast cancer result in the most deaths. Here we integrate observed cancer statistics and trends with observed and estimated US demographic data to project cancer incidences and deaths to the year 2040. Methods: Demographic cancer-specific delay-adjusted incidence and death rates from the Surveillance, Epidemiology, and End Results Program (2014-2016) were combined with US Census Bureau population growth projections (2016) and average annual percentage changes in incidence (2011-2015) and death (2012-2016) rates to project cancer incidences and deaths through the year 2040. We examined the 10 most incident and deadly cancers as of 2020. We utilized Joinpoint analysis to examine changes in incidence and death rates over time relative to changes in screening guidelines. Results: We predict the most incident cancers in 2040 in the US will be breast (322,000 diagnoses in 2040) and lung (182,000 diagnoses in 2040) cancer. Continuing decades long observed incident rate trends we predict that melanoma (173,000 diagnoses in 2040) will become the 3rd most common cancer while prostate cancer (63,000 diagnoses in 2040) will become the 5th most common cancer after colorectal cancer (139,000 diagnoses in 2040). Lung cancer (61,000 deaths in 2040) is predicted to continue to be the leading cause of cancer related death, with pancreas (45,000 deaths in 2040) and liver & intrahepatic bile duct (38,000 deaths in 2040) cancer surpassing colorectal cancer (34,000 deaths in 2040) to become the second and third most common causes of cancer related death, respectively. Breast cancer deaths (29,000 in 2040) are predicted to continue to decrease and become the fifth most common cause of cancer death. Joinpoint analysis of incidence and death rates supports a significant past, present, and future impact of cancer screening programs on the number of cancer diagnoses and deaths, particularly for prostate, thyroid, melanoma incidences, and lung cancer deaths. Conclusions: We demonstrate marked changes in the predicted landscape of cancer incidence and deaths by 2040. Our analysis reveals an influence of cancer screening programs on the number of cancer diagnoses and deaths in future years. These projections are important to guide future research funding allocations, healthcare planning, and health policy efforts.
Is there a genomic fingerprint of Radon (Rn)-induced lung cancer (LC)? Comparison of genomic alterations in LC specimens from high and low Rn zones.
Authors: Khan Hina , Saiganesh Harish , Olszewski Adam J. , Baca Yasmine , Kastura Michaela , Vatkevich John , Patel Nimesh , Khurshid Humera , Birnbaum Ariel E. , Liu Stephen V. , Mamdani Hirva , Kim Chul , Vanderwalde Ari M. , Raez Luis E. , Socinski Mark A. , Lopes Gilberto , Pai Sachin Gopalkrishna , Nieva Jorge J. , Azzoli Christopher G. , Safran Howard
Published: May 2020

1572

Background: Rn-222 is a radioactive gas found in rocks and soil. It emits alpha particles that cause dsDNA breaks and increase potential for carcinogenesis. Rn is the 2nd leading cause of LC in the US after smoking. EPA estimates >15,000 deaths/yr (9% of LC deaths) from Rn. We hypothesize that the impact of Rn exposure may be reflected in LC gene mutation (mut) profiles. Methods: Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in FFPE specimens from 159 LC patients (pts) from the Lifespan Cancer Institute in Rhode Island (2014- 2019), followed by validation in a larger cohort of 5,532 pts using Caris platform. Based on EPA Rn maps, we identified counties with high indoor Rn levels (>4 pci/L; HR), and compared gene mut patterns with those from low Rn zones (<4 pci/L; LR). Based on pt’s zip code of residence, we categorized them to HR and LR. In the validation cohort, p values adjusted for multiple comparison (q) of < .05 were considered significant. Results: In the pilot cohort, 35 pts (22%) were in HR and 124 (78%) in LR zones. Adenocarcinoma histology was most frequent (73%) and smoking prevalence was high (75%) in both groups. Most prevalent alterations were TP53, KRAS and CDKN2A muts. In the HR, we noted more frequent recurrent muts in 2 DNA repair genes (DDR): ATM (11 vs 1%, p= .00086) and CHEK2 (6 vs 0%, p= .047) when compared to LR group. When classified into major pathways implicated in lung carcinogenesis, higher frequency of mutations were seen in DDR in HR zones vs. LR (29 vs 13%, p= .038). In the validation cohort, 1,433 (26%) pts were in HR and 4099 (74%) in LR zones. Among the DDR genes, ATM muts in HR group tended to be more frequent (4.7 vs 3.4% in LR, p= .03) as well as PALB2 (0.9 vs 0.4%, p= .02) while no difference seen in CHEK2. Other genes with significantly higher prevalence in HR were TP53, SMARCA4 and NFE2L2 (q< .05); while KMT2D, KEAP1, CDKN2A, MET, NF2, DNMT3A, CCND1 and FAS show a trend (p< .05). EGFR muts were significantly more frequent in LR zones (8.4 vs 14.6%, q= .001). Similar to the pilot cohort, DDR pathway alterations trend to be higher in HR zones (14 vs 12%, p= .05). Using a high TMB cut-off >10, tumors from HR zones had significantly higher TMB when compared to LR zones (56 vs 48%, q= .0005). Conclusions: To our knowledge, this is the first attempt to elucidate the pathobiology of Rn induced LC using gene mut analyses. Our observations suggest that LC associated with higher Rn exposure may have disabled DNA repair pathways and higher TMB. Assuming uniform tobacco smoke exposure, higher Rn was not associated with EGFR mut.