bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of GC4419 (avasopasem manganese) on chronic kidney disease in head and neck cancer patients treated with radiation and cisplatin.
Authors: Steinbach Emily J. , Monga Varun , Furqan Muhammad , Laux Douglas Earl , Zepeda-Orozco Diana , Jetton Jennifer G. , Saunders Deborah , Dunlap Neal , Curtis Amarinthia , Fairbanks Robert , Bell Sarah , Anderson Carryn M. , Beardsley Robert Alan , Holmlund Jon , Spitz Douglas , Allen Bryan G.
Published: May 2020

12071

Background: Nephrotoxicity is a major complication of platinum-based chemotherapy and ranges in incidence from 31-68%. The effects of platinum-based chemotherapeutics on long-term renal outcomes (chronic kidney disease, CKD) profoundly affect morbidity and mortality. Concurrent chemoradiotherapy (CRT) including cisplatin is standard for locally advanced squamous cell head and neck cancer (HNC) but is accompanied by the risk of CKD. In a randomized, multi-center, placebo-controlled Phase 2b trial ( NCT02508389 ) of GC4419 (avasopasem manganese) in HNC patients receiving CRT, avasopasem reduced the duration, incidence, and severity of severe oral mucositis (Anderson et al, JCO 2019). Avasopasem did not appear to alter the safety profile of CRT in that trial, including incidence of adverse events of kidney injury or azotemia. Methods: Pre- and post-treatment markers of kidney function including blood urea nitrogen (BUN), serum creatinine (sCr), and estimated glomerular filtration rate (eGFR) were retrospectively evaluated for a subset of 52 of the trial patients who received 3 cycles x 100 mg/m2 cisplatin plus placebo or 30 or 90 mg of avasopasem intravenously prior to RT, and 7 comparator patients who received the same CRT outside the study. Kidney function was evaluated between 3- and 24-months post-completion of cisplatin-radiation therapy by two-way analysis of variance (ANOVA) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) CKD staging. Results: Baseline patient characteristics were skewed towards a male population but were balanced across all treatment arms with regards to baseline kidney function (comparator + placebo, n = 19; 30 mg GC4419, n = 18; 90 mg GC4419, n = 15). Treatment with 90 mg GC4419 demonstrated normal BUN values (10-20 mg/dL) at 3, 6, and 18 months and normal sCr values (0.6-1.2 mg/dL) between 3 and 24 months as compared to the placebo arm + comparator group, which exhibited statistically elevated BUN and sCr (p < 0.05). Treatment with 90 mg GC4419 also demonstrated significantly higher eGFR between 3 and 24 months post-chemoradiation (p < 0.05) compared to the placebo arm + comparator group. 90 mg GC4419 treatment significantly reduced the incidence of CKD compared to the placebo arm and comparator group, as determined by fold change in sCr values and eGFR measurements < 60 mL/min (stage G3a/b, G4, or G5 CKD). Conclusions: Avasopasem has the potential to reduce the incidence and severity of CKD in patients receiving cisplatin therapy. Clinical trial information: NCT02508389 .
Cutaneous pigmentary changes related to anticancer therapy in African Americans.
Authors: Barrios M.S Dulce M. , Noor Sarah J. , Lacouture Mario E.
Published: May 2020

12074

Background: Pigmentary disorders are known to disproportionately affect individuals with darker skin, including African Americans (AAs)— a historically underrepresented population in oncology research. However, reports on the prevalence and characterization of anticancer-therapy related cutaneous pigmentary changes in this population are lacking. Methods: A retrospective analysis of AA cancer patients that ever received a hematopoietic stem cell transplantation (HSCT) and/or systemic oncologic therapy within six months prior to diagnosis of cutaneous hypo- or hyperpigmentation at our institution between 4/18/2012 and 8/26/2019 was conducted. Clinical and management characteristics were summarized; severity of pigmentary changes was assessed using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0). Results: From a total of 1342 AA patients evaluated by oncodermatologists during the study period, 121 (9%) met inclusion criteria. Average age in this cohort was 52, and 102 (84%) were women. Breast (63, 52%), gastrointestinal (14, 12%), and hematologic malignancies (13, 11%) comprised the majority of cancer diagnoses. Most (93, 77%) patients had skin hyperpigmentation (84, 69%) or hypopigmentation (9, 7%) as a primary CTCAE diagnosis; the rest had secondary post-inflammatory hyperpigmentation (28, 23%). A higher proportion (105, 87%) of pigmentary alterations was attributed to single agents [i.e. chemo- (55, 46%), radiation (16, 13%), targeted (12, 10%), endocrine (9, 7%), and supportive oncologic (6, 5%) therapy] versus combination treatment (16, 13%). Five (4%) patients had graft versus host disease associated with allogeneic HSCT, four (80%) of which presented as cutaneous hypopigmentation. Hand foot syndrome (24, 20%), acneiform rash (24, 20%), and radiation dermatitis (16, 13%) were commonly diagnosed dermatologic adverse events (dAEs), generally classified as mild/grade 1 (67, 55%) in severity. For management, skin lightening agents +/- emollients (36, 30%) or emollients alone (25, 21%) were highly recommended. Topical corticosteroids +/- emollients were prescribed just as frequently as reassurance and/or avoidance of sun exposure (22, 18%). Conclusions: Cutaneous pigmentary changes related to cytotoxic chemotherapy, radiation and/or targeted oncologic therapy are common in AA cancer patients. Undertreatment of these dAEs, possibly due to under-recognition in darker skin, warrants further investigation to assess impact on quality of life and help improve management in this population.
Patient-reported distress and healthcare utilization in patients with advanced cancer.
Authors: Hildenbrand Jordan Danielle , Park Heesu , Casarett David , Ellis Alicia , Herring Kris , Kamal Arif , Power Steve , Troy Jesse D , Wolf Steven , Zafar Yousuf , LeBlanc Thomas William
Published: May 2020

12093

Background: The National Comprehensive Cancer Network (NCCN) defines distress as an unpleasant, multidimensional experience that may interfere with patient behavior, emotions, and ability to cope with illness. Distress screening is a critical aspect of comprehensive cancer treatment, but the relationship between patient-reported distress and healthcare utilization remains unclear. We assessed this relationship in patients with advanced cancers historically associated with high utilization, specifically non-small cell lung cancer (NSCLC) and non-colorectal gastrointestinal (NCRGI) cancer. Methods: We extracted data from the electronic medical record of adult patients with metastatic NSCLC and NCRGI cancers who were receiving active treatment, visited outpatient Duke Cancer Institute clinics between July 2013 and January 2017, and completed at least two self-report NCCN Distress Thermometer (DT) and Problem List (PL) surveys as part of routine clinical care between July 2013 and March 2019. Mixed effects logistic regression was used to estimate the odds of hospitalization or emergency room (ER) visit within either 3 or 6 months after each self-reported DT, with adjustment for age at first distress score, sex, primary tumor site, race (white vs. non-white) and duration of participation (i.e., time from first distress score to 3 months after the last distress score) information from the EMR. Results: A total of 11,027 DT scores were collected from 848 patients, with 508 (60%) having NSCLC, 340 (40%) having NCRGI cancer, and 192 (23%) reporting actionable distress (i.e., DT score ≥4). Actionable distress was associated with higher odds of hospitalization or visiting the ER within 3 months (OR = 1.37; 95% CI = 1.19, 1.58; p < 0.001) and 6 months (OR = 1.19; 95% CI = 1.03, 1.37; p = 0.019) after DT self-report. Patients who had an average DT score of ≥4 were more likely to report the following problems at least once: worry (89% of patients), nervousness (79%), fatigue (95%), pain (92%), sleep problems (79%), and eating problems (79%). Conclusions: Patient-reported distress is associated with greater healthcare utilization in patients with advanced NSCLC and NCRGI cancers who are receiving active treatment. These patients report high burden of physical and emotional problems. Actionable distress may be a useful indicator of patients in need of specialist palliative care interventions.
Scalp cooling to prevent chemotherapy induced alopecia (CIA) in black patients: Differences in efficacy?
Authors: Dilawari Asma Ali , Alintah Princess , Paxman Richard , Chitalia Ami , Gallagher Christopher , Tiwari Shruti Rakesh , Dash Chiranjeev , Adams-Campbell Lucile L.
Published: May 2020

12101

Background: The Paxman scalp cooling device has been used for over 20 years to prevent CIA, obtaining FDA clearance in the U.S. in 2017. Prior studies reported 50-80% success and high patient satisfaction yet included few or no black patients. In the U.S. this may reflect disparities in access due to cost, awareness, or availability. We opened a prospective observational study combining patient-reported outcomes with clinical assessments of alopecia and planned to deliver scalp cooling to 30 black patients receiving chemotherapy for breast cancer. Methods: Patients who self-identified racially as black, had a new diagnosis of stage I-III breast cancer, and planned to receive chemotherapy with taxane-containing regimens were eligible. Anthracycline (AC) and non-anthracycline (NAC) chemotherapy agents were included; costs for the intervention were covered by Paxman and internal philanthropic funding. Patients who declined scalp cooling were approached for enrollment as controls. Primary endpoints were grade of alopecia as measured by providers and patient self-report using Modified Dean Scale and Visual Analog Scale (VAS) respectively. Hair preservation was defined as <50% hair loss (<grade 2) by Dean and score < 50 on VAS. Secondary endpoints were alopecia by NCI grading scale and psychosocial from CADS and EORTC QLQ BR45 questionnaires. Results: 15 out of 30 planned participants enrolled by February 2020 with interim analysis and hold in accrual due to lack of efficacy. Four patients remain on treatment. Of 11 scalp cooling patients who completed chemotherapy, 0 prevented significant alopecia. Nine discontinued use of scalp cooling before completion (1 due to scheduling, 8 due to >grade 3 alopecia). The 2 patients who used scalp cooling for the duration had >grade 3 alopecia before the last cycle of treatment. Conclusions: Scalp cooling is an important supportive therapy that can reduce chance of alopecia, a bothersome side effect for patients. Our experience indicates decreased efficacy in black patients with both AC and NAC regimens. This is an important negative result to explore. Discussions with the Paxman team and providers with expertise in alopecia are underway to explore contributing factors such as hair thickness, prior hair treatments, and cap design. [Table: see text]
Palliative referrals in advanced cancer patients: Utilizing the Supportive and Palliative Care Indicators Tool and Rothman Index.
Authors: Chan Abigail Sy , Rout Amit , Lev Irina , Yu Amy , D'Adamo Chris , Miller Kenneth David
Published: May 2020

12102

Backgroun1d: Timely identification of palliative care needs have the ability to reduce hospitalizations and improve QOL. The Supportive & Palliative Care Indicators Tool (SPICT) is used to identify patients with advanced stage medical conditions who may need special care planning. The Rothman Index (RI) detects patients at high risk of acutely decompensating in the inpatient setting and has been validated to assess 24-hour mortality risk. We used SPICT and RI in cancer patients admitted to the hospital and evaluated their roles in recognizing early palliative care needs and 6-month mortality. Methods: Advanced/metastatic cancer patients admitted to our institution from Jan 1, 2019 to June 30, 2019 were retrospectively reviewed. Patient demographics, length of hospital stay (LOS), comorbidities, palliative/hospice care referrals, vital status, initial RI score, and computed SPICT scores were obtained. Worse clinical indicators were defined as SPICT positive if it met > 2 clinical indicators or RI < 60. Univariate and bivariate analyses were performed. Results: A total of 227 patients were included, mean age 68, 34% Caucasians, 63% Blacks, 59% female, median comorbidities of 3, with majority having lung and GI malignancies. A total of 137 (60%) were SPICT +, 47 (21%) had RI < 60, and 38 (17%) concurrent SPICT + and RI < 60. SPICT + patients were more likely to have longer hospital stay, change in code status, more palliative/hospice referrals, and increased mortality. Those with RI < 60 had similar results (Table). SPICT + patients are more likely to have RI < 60 (p = 0.0013). Conclusions: SPICT and RI are valuable tools in predicting 6-month mortality and palliative/hospice care referrals. These can also be utilized to initiate early palliative and goals of care discussions in patients with advanced cancer. [Table: see text]
A survey of cannabis use for symptom palliation in breast cancer patients by age and stage.
Authors: Weiss Marisa C. , Buckley Meghan , Hibbs Julianne , Leitenberger Adam , Jenkins Melissa , McHugh Terri W. , Green Nancye , Larson Sharon
Published: May 2020

12108

Background: Most US states have legalized medical cannabis for the treatment of serious conditions, including cancer. It is not well known which symptoms breast cancer patients seek to control with cannabis. Methods: Members of the Breastcancer.org and Healthline communities were invited to participate in this survey between 12/16/2019 and 1/19/2020. Eligibility criteria included age ≥18 years, resident of the US and a breast cancer diagnosis within the past 5 years. Eligible respondent data were analyzed for the symptomatic profile of cannabis users. Symptoms were compared between two groups using a Chi-square test of independence. The survey was led by Socanna, conducted by Outcomes Insights, and supported by a grant from Ananda Health/Ecofibre. Results: Among the 832 respondents who completed screening, 725 met the eligibility criteria, and 612 (84%) completed the survey. The median age of respondents was 57 years, and 85% had non-metastatic disease An estimated 42% of respondents have used medical cannabis to treat symptoms or side effects of breast cancer. Medical cannabis users reported using cannabis to treat insomnia (70%), joint and muscle aches, discomfort, stiffness, or pain (59%), anxiety (57%), and stress (51%). The medical cannabis users less than 50-year-old were more likely to use cannabis to treat these symptoms than their over 50-year-old counterparts, however, the differences were not statistically significant. Medical cannabis users under age 50 used cannabis significantly more than over 50 to treat nausea/vomiting (58% vs 40%; p = 0.010) and inflammation (34% vs 20%; p = 0.021). Medical cannabis users with metastatic disease were more likely to use medical cannabis to treat chronic pain 60% vs 41%; p = 0.017) than non-metastatic users. Post-surgery patients were most likely to use cannabis for nerve pain; and those who were beyond treatment, for stress. Patients suffered an average of 5 symptoms. Conclusions: A significant proportion of breast cancer patients reported using cannabis to treat a combination of symptoms from their cancer and its treatment. Although younger patients are somewhat more likely to use this form of palliative management, older patients are suffering from the same symptoms and their use is nearly as high. More research is needed on the personalization of safe and effective symptomatic management with medical cannabis, for people of all ages, stages, and forms of treatment.
The Quebec Cannabis Registry: a pharmacovigilance and effectiveness study on the use of medical cannabis in cancer patients.
Authors: Vigano Antonio , Canac-Marquis Michelle , Gamaoun Rihab , Beaulieu Pierre , Neron Andrée , Moride Yola , Martell Marc O , Desroches Julie , Perez Jordi
Published: May 2020

12109

Background: The Quebec Cannabis Registry (QCR) was launched in 2015 to allow physicians to prescribe medical cannabis (MC) in the province of Quebec, Canada. This study aimed to investigate the safety and effectiveness of MC in cancer patients using pharmacovigilance data prospectively collected for up to 24 months. Methods: Patients were enrolled in the QCR between May 2015 and October 2018 and followed every 3 months. Study outcomes included adverse events (AE), pain severity and interference (Brief-Pain Inventory), wellbeing (Revised-Edmonton Symptom Assessment Scale) and overall health scale (EQ5D5L) at baseline and at each follow-up (F-UP). Significance of changes over time were assessed using repeated-measures ANOVA. Results: Out of the 2991 patients enrolled in the QCR, 358 (12.8%) were cancer patients (mean age 57.7 (± 14.6); 171 (47.8%) males). The main cancer types were breast (16.2%), lung (11.7%), leukemia (11.5%) and colorectal (11.2%). MC was prescribed primarily for pain (72.1%), anxiety (4.7%), nausea (4.5%), anorexia (3.9%), and insomnia (3.1%). A total of 13 patients (3.6%) reported AE with only three being serious (one unrelated to MC: stroke; and two possibly related: diarrhea, from CBD oil overdose and pneumonia from smoking MC). Mean scores significantly (p < 0.05) improved between baseline and 3 months F-UP for pain severity (4.8 ± 1.5 vs 4.1 ± 1.8), pain interference (4.6 ± 1.8 vs 3.8 ± 1.7), and the overall health scale (60 ± 21 vs 71 ± 18). Well-being scores also significantly improved between baseline and 6 months F-UP (4.4 ± 2.1 vs 3.5 ± 2.8). Conclusions: Population-based data shows that cancer patients can benefit safely and effectively from MC as a complementary treatment, when prescribed and monitored under medical-nursing supervision.
Defining patient-elicited concepts unique to adolescents and young adults with cancer.
Authors: Avutu Viswatej , Lynch Kathleen , Barnett Marie , Vera Jacqueline , Glade Bender Julia Lynne , Tap William D. , Atkinson Thomas Michael
Published: May 2020

12118

Background: Adolescents and young adults (AYAs) require a multidisciplinary approach to cancer care due to complex biopsychosocial variables and varied developmental maturity. Currently, age and diagnosis determine referral to pediatric or adult oncology with differing care paradigms and service utilization. These issues, in conjunction with differences in tumor biology and lower accrual to clinical trials, have contributed to marginal improvements in outcomes for AYAs. Compounding this dilemma is a lack of validated patient-reported outcome measures (PROs) for AYAs. Tracking standardized PROs longitudinally is a crucial step in understanding psychosocial variables, identifying tailored needs, improving outcomes and standardizing care. However, developing a PRO tool for AYAs first requires identifying AYA-unique domains. Methods: Three, 90-minute focus groups were conducted with AYAs treated at Memorial Sloan Kettering in the context of 1) pediatric oncology, 2) medical oncology, and 3) either service. Topics explored included: experiences of cancer care as an AYA; physical, social and emotional concerns; and information needs, including appropriateness, timing, and depth of information. Thematic content analysis of transcripts was performed by four interdisciplinary coders in weekly iterative consensus rounds. Phase one consisted of identification of key domains to guide line-by-line coding with NVivo software. Phase two consisted of independent review and categorization of codes, followed by three successive consensus meetings to identify distinct themes. Results: A mean of 6 patients (range 5-7) participated in each of the 3 groups; the total sample (n = 17) included 9 males and 8 females, ages 19-35 years (median 26). Four AYA-unique themes were identified: 1. AYAs have an uncertain sense of the future and desire more engagement in conversations pertaining to survivorship, long-term effects and transition to outpatient life. 2. Cancer as an AYA is a socially-isolating experience, prompting a strong desire to connect with peers during and post-treatment. 3. AYAs want control over who can be present during discussions with their care team as the presence of loved ones can impede or facilitate communication. 4. AYAs may be living far away from loved ones during treatment and lack supports needed to help them navigate treatment and daily life. Conclusions: Concept elicitation via focus groups identified novel themes related to survivorship, isolation, communication and social support, which can inform development of AYA-specific PROs.
Performance of the IBIS/Tyrer-Cuzick (TC) Model by race/ethnicity in the Women’s Health Initiative.
Authors: Kurian Allison W. , Hughes Elisha , Bernhisel Ryan , Probst Braden , Lanchbury Jerry , Wagner Susanne , Gutin Alexander , Caswell-Jin Jennifer Lee , Rohan Thomas E , Shadyab Aladdin H. , Manson JoAnn E , Lane Dorothy , Stefanick Marcia L.
Published: May 2020

1503

Background: The TC model, a breast cancer (BC) risk assessment tool based on family cancer history, reproductive and lifestyle factors is used to guide BC screening and prevention. TC was developed and validated largely in non-Hispanic White (NHW) women. We evaluated the calibration and discrimination of TC version 7.02 among racially/ethnically diverse post-menopausal women enrolled in the Women’s Health Initiative (WHI) clinical trials or observational study. Methods: WHI enrolled post-menopausal women from 1993-1998 and followed them prospectively for BC incidence. We included women aged ≤80 years at enrollment with no prior BC or mastectomy and with data required for TC, including weight, height, ages at menarche, first birth and menopause, menopausal hormone therapy use and family history of breast or ovarian cancer in first or second-degree relatives. Calibration was assessed by the ratio of observed BC cases to the number expected by TC (O/E), with expected cases calculated as the sum of cumulative hazards. We tested for differential discrimination by race/ethnicity (NHW, African American, Hispanic, Asian/Pacific Islander, Native American, other) using Cox regression. Time to BC was modeled using age, race/ethnicity, TC estimate (transformed by log of relative lifetime risk), and a term for interaction between race/ethnicity and TC estimate. Results: During the follow-up period (median 18.9 years, maximum 23.4 years), 6,836 new BC cases were diagnosed among 91,893 women. TC was well-calibrated overall (O/E 0.95) in NHW and African Americans, but over-estimated risk for Hispanics (O/E 0.75, Table). Results suggested good calibration for Asian/Pacific Islanders and Native Americans, but sample sizes were small. Discrimination did not differ significantly by race/ethnicity (two-sided p-value for interaction = 0.33). Conclusions: TC provided similar risk discrimination among post-menopausal women of different racial/ethnic groups over nearly 20 years of follow-up; however, it overestimated risk for Hispanics. Future studies in diverse populations are warranted, with need for a more accurate breast cancer risk assessment tool for Hispanics. [Table: see text]
A randomized controlled trial of video-education or in-person genetic counseling for men with prostate cancer (ProGen).
Authors: Rana Huma Q. , Stopfer Jill E. , Petrucelli Nancie , Koeller Diane R. , Pirzadeh-Miller Sara , Reys Brian , Kipnis Lindsay , Culver Samantha , Vatnick Donna Rachel , Silver Rebecca , Mercado Joanna , Gelman Rebecca Sue , Weitz Michelle , Speare Virginia , Dolinsky Jill S. , Heath Elisabeth I. , Ross Theodora Suzanne , Courtney Kevin Dale , Garber Judy Ellen , Taplin Mary-Ellen ,   ProGen Study Team
Published: May 2020

1507

Background: Approximately 10% of men with advanced prostate cancer (PC) have pathogenic/likely pathogenic variants (PV) in cancer susceptibility genes and their identification may lead to targeted therapy. Genetic testing (GT) can also guide cancer surveillance and prevention for family members. While GT is recommended for men with potentially lethal PC, traditional testing models are strained, and access limited. The ProGen study examined a novel pretest model aimed at providing access to GT while promoting informed consent. Methods: Inclusion criteria were: potentially lethal PC (metastatic, localized with Gleason score ≥8, rising/persistent PSA after local therapy), diagnosis age ≤ 55 years, prior malignancy, family history suggestive of a PV and/or at oncologist’s discretion. Consented subjects from 3 sites were randomized 3:1 to video education (VE) or in-person genetic counseling (GC). Subjects who consented to GT had 67 genes analyzed (Ambry, USA) with results disclosed by telephone by a genetic counselor. Outcomes included GT uptake, PV prevalence, and survey measures of satisfaction, distress, genetics knowledge, family communication, and impact on cancer care (obtained at the time of intervention, and at 1, 4, and 12 months after result disclosure). Two-sided Fischer exact tests were used for between-arm comparisons. Results: Over a 2-year period: 662 subjects were randomized, VE or GC were completed by 604 subjects (VE: 93.1%, GC: 88.8%) of whom 596 subjects (VE:98.9%, GC:97.9%) consented to GT. To date, 591 subjects have completed GT (VE: 99.3%, GC: 98.6%). At the time of intervention, most subjects agreed or strongly agreed that their assigned arm was useful (VE: 95%, GC: 88%). Differences were not statistically significant. Notably, 84 PV were identified in 78 subjects (13.2%), with BRCA1/2 PV accounting for 32% of subjects with a positive result ( BRCA2:21, BRCA1:4). Conclusions: In this randomized trial, both novel VE and traditional GC yielded high GT uptake without significant differences in outcome measures of acceptability and satisfaction. VE enabled access to critical GT results while maintaining the core tenants of informed consent. PV were found in 13.2% of subjects, 32% of whom had BRCA1/2 PV. Analysis of collected survey data to inform strengths and limitations of VE as compared with pretest GC will be presented. Clinical trial information: NCT03328091.
Expanding the diagnostic yield of germline genetic testing in cancer patients using deep learning.
Authors: Aldubayan Saud H , Conway Jake , Witkowski Leora , Kofman Eric , Reardon Brendan , Camp Sabrina , Han Seunghun , Elmarakeby Haitham , Al-Rubaish Abdullah , Al-Sulaiman Abdulsalam , Al-Ali Amein , Taylor-Weiner Amaro , Van Allen Eliezer Mendel
Published: May 2020

1518

Background: Germline genetic analysis is an essential tool for implementing precision cancer prevention and treatment. However, only a small fraction of cancer patients, even those with features suggestive of a cancer-predisposition syndrome, have detectable pathogenic germline events, which may in part reflect incomplete pathogenic variant detection by current gold-standard methods. Here, we leveraged deep learning approaches to expand the diagnostic utility of genetic analysis in cancer patients. Methods: Systematic analysis of the detection rate of pathogenic cancer-predisposition variants using the standard clinical variant detection method and a deep learning approach in germline whole-exome sequencing data of 2367 cancer patients (n = 1072 prostate cancer, 1295 melanoma). Results: Of 1072 prostate cancer patients, deep learning variant detection identified 16 additional prostate cancer patients with clinically actionable pathogenic cancer-predisposition variants that went undetected by the gold-standard method (198 vs. 182), yielding higher sensitivity (94.7% vs. 87.1%), specificity (64.0% vs. 36.0%), positive predictive value (95.7% vs. 91.9%), and negative predictive value (59.3% vs. 25.0%). Similarly, germline genetic analysis of 1295 melanoma patients showed that, compared with the standard method, deep learning detected 19 additional patients with validated pathogenic variants (93 vs. 74) with fewer false-positive calls (78 vs. 135) leading to a higher diagnostic yield. Collectively, deep learning identified one additional patient with a pathogenic cancer-risk variant, that went undetected by the standard method, for every 52 to 67 cancer patients undergoing germline analysis. Superior performance of deep learning, for detecting putative loss-of-function variants, was also seen across 5197 clinically relevant Mendelian genes in these cohorts. Conclusions: The gold-standard germline variant detection method, universally used in clinical and research settings, has significant limitations for identifying clinically relevant pathogenic disease-causing variants. We determined that deep learning approaches have a clinically significant increase in the diagnostic yield across commonly examined Mendelian gene sets.
Performance of polygenic risk scores for cancer prediction in an academic biobank.
Authors: Desai Heena , Le Anh , Hausler Ryan , Verma Shefali , Verma Anurag , Judy Renae , Doucette Abigail , Gabriel Peter Edward , Damrauer Scott , Ritchie Marilyn , Rader Daniel , Kember Rachel , Maxwell Kara Noelle ,   Regeneron Genetics Center
Published: May 2020

1528

Background: The discovery of rare genetic variants associated with cancer have a tremendous impact on reducing cancer morbidity and mortality when identified; however, rare variants are found in less than 5% of cancer patients. Genome wide association studies (GWAS) have identified hundreds of common genetic variants significantly associated with a number of cancers, but the clinical utility of individual variants or a polygenic risk score (PRS) derived from multiple variants is still unclear. Methods: We tested the ability of polygenic risk score (PRS) models developed from genome-wide significant variants to differentiate cases versus controls in the Penn Medicine Biobank. Cases for 15 different cancers and cancer-free controls were identified using electronic health record billing codes for 11,524 European American and 5,994 African American individuals from the Penn Medicine Biobank. Results: The discriminatory ability of the 15 PRS models to distinguish their respective cancer cases versus controls ranged from 0.68-0.79 in European Americans and 0.74-0.93 in African Americans. Seven of the 15 cancer PRS trended towards an association with their cancer at a p<0.05 (Table), and PRS for prostate, thyroid and melanoma were significantly associated with their cancers at a bonferroni corrected p<0.003 with OR 1.3-1.6 in European Americans. Conclusions: Our data demonstrate that common variants with significant associations from GWAS studies can distinguish cancer cases versus controls for some cancers in an unselected biobank population. Given the small effects, future studies are needed to determine how best to incorporate PRS with other risk factors in the precision prediction of cancer risk. [Table: see text]
Functional analysis of patient-derived PALB2 missense variants of uncertain significance.
Authors: Wu Shijie , Zhou Jiaojiao , Chen Yiding
Published: May 2020

1531

Background: Inherited PALB2 pathogenic variants are associated with an increased lifetime risk for breast cancer development. However, the interpretation of numerous PALB2 missense variants of uncertain significance (VUS) identified in germline genetic testing remains a challenge. Here, we assessed the impact of breast cancer patient-derived VUS on PALB2 function and identified pathogenic PALB2 missense variants that may increase cancer risk. Methods: A total of seven potentially pathogenic PALB2 VUS identified in 2,279 breast cancer patients were selected for functional analysis. All these selected VUS were assessed by SIFT, Align-GVGD, and PolyPhen2 in silico and were predicted to be deleterious by at least two in silico algorithms. The p.L35P [c.104T > C] variant was also included, for which pathogenicity has been recently confirmed. The effects of the VUS on the homologous recombination (HR) activity of PALB2 were tested by U2OS/DR-GFP reporting system. Functional characterization was further validated by protein co-immunoprecipitation and RAD51 recruitment assay. Results: PALB2 variants p.L24F [c.72G > C] and p.L35P [c.104T > C] showed the most significant disruption to the HR activity of PALB2 relative to the wild-type condition, retaining only 52.2% ( p = 0.0013) and 8.5% ( p < 0.0001) of HR activity respectively. Moderate but statistically significant HR deficiency was observed for four other variants (p.P405A [c.1213C > G], p.T1012I [c.3035C > T], p.E1018D [c.3054G > C], and p.T1099M [c.3296C > T]). We found no statistical differences for the p.K628N [c.1884G > T] and p.R663C [c.1987C > T] in the HR activity compared to wild-type PALB2. The p.L24F and p.L35P variants compromised the BRCA1-PALB2 interaction and reduced RAD51 foci formation in response to DNA damage. Conclusions: We have identified a novel patient-derived pathogenic PALB2 missense variant, p.L24F [c.72G > C], that compromises PALB2-mediated HR activity. We suggest the integration of the identified pathogenic variants into breast cancer genetic counseling and individualized treatment regimens for better clinical outcomes.
Five year letrozole versus placebo in BRCA1/2 germline mutations carriers: Final results of LIBER, a double-blind randomized phase III breast cancer prevention trial.
Authors: Pujol Pascal , Roca Lise , Lortholary Alain , Lasset Christine , Dugast Catherine , Berthet Pascaline , Tennevet Isabelle , Fricker Jean-Pierre , Nathalie Chabbert-Buffet , Gesta Paul , This Pascale , Chiesa Jean , N'Guyen TD , Mailliez Audrey , Venat-Bouvet Laurence , Dreyfus Hélène , Delnatte Capucine , Galibert Virginie , Lemonnier Jerome , Delaloge Suzette
Published: May 2020

1534

Background: Women with germline BRCA1/2 (gBRCA1/2) mutations have a 70% lifetime risk of breast cancer (BC). Medical prevention by aromatase inhibitors is effective in high-risk patients (pts), including those with familial risk. However, hormone prevention has not been specifically addressed in women (wn) carrying gBRCA1/2 mutations. Methods: LIBER is a randomized, double-blind, placebo-controlled phase III trial evaluating 5-year treatment with letrozole 2.5 mg/day (L) versus placebo (P) on decreasing BC incidence in post-menopausal women with gBRCA1/2 mutations ( NCT00673335 ). Eligible wn were aged 40-70 and could have had unilateral BC > 5 years ago. Randomization was stratified on mutation ( BRCA1/BRCA2), bilateral oophorectomy and history of prior BC. Primary endpoint was 5-year invasive BC-free survival (BC-FS) in wn with or without previous BC. Main secondary endpoints were safety and quality of life (menopause rating scale, SF36). 270 pts were required to observe 37 events to show a gain in 5-year invasive BC-FS from 80% to 92% (HR=0.35) with 1-sided α=0.05 and 90% power. Results: 170 wn were randomized from 02/2008 to 02/2013; 86 and 84 were assigned to the P and L arm. Median age was 55 years (range 40-70). Pt characteristics were well balanced; 59% and 41% carried gBRCA1 and gBRCA2 mutations. In P and L arms, 47% and 43% had prior BC, 43% and 42% stopped treatment prematurely, 37 and 23 serious adverse events occurred, and during active treatment, 8 and 10 wn had grade 3/4 toxicity. Median follow-up was 72.7 months. Five-year BC-FS did not significantly differ between the P and L arms (92% vs 91%, HR 0.83; 95%CI: 0.3-2.3, p=0.73) in the overall population, nor in the subgroups of wn with and without previous BC (74% vs 91%; HR 0.43; 95% CI: 0.1-1.3; 90% vs 86%; HR 1.29; 95% CI 0.4-3.9), gBRCA1 versus gBRCA2 or hormone receptor-positive BC. Letrozole had no effect on quality of life. The two groups did not significantly differ in bone density, which decreased over time in the overall population. Conclusions: In this prospective preventive trial, BC-FS was not significantly decreased by letrozole versus placebo in women with BRCA1/2 mutations. However, the study was underpowered (170 of 270 pts expected). Despite no differences in safety and quality of life, drop-out rate was high in both P and L arms. Clinical trial information: NCT00673335.
Return of results after somatic tumor mutation profiling in advanced cancer: Psychological impacts.
Authors: Butow Phyllis , Davies Grace , Napier Christine , Thomas David Morgan , Bartley Nicole , Goldstein David , Ballinger Mandy L. , Juraskova Ilona , Schlub Timothy E , Tucker Kathy , Meiser Bettina , Young Mary-Anne
Published: May 2020

1541

Background: Somatic tumor mutation profiling (STMP) is entering clinical practice. We aimed to investigate psychological impacts of receiving results. Methods: Eligible participants had: advanced solid cancers of any histological type; accessible tissue for STMP; and enrolled in the Molecular Screening and Therapeutics (MoST) Program. 1074 participants (91%) completed a baseline assessment prior to STMP (T0), of whom 570 (47%) received results and completed a post-result assessment (T1) of impact of genetic results (MICRA), anxiety and depression (HADS), cancer-specific anxiety (IES), and satisfaction with decision to have STMP. Linear regression models controlling for age, gender, parental status, cultural diversity, education and ECOG status explored associations between result received and psychological outcomes. Results: 360 participants received an actionable result and were recommended personalised treatment: 152 via a MoST sub-study (G1) and 208 via their treating oncologist (G2). 210 received a non-actionable result (G3). At T1, G3 were significantly more distressed and less positive about their result (MICRA subscales) and less satisfied with their decision to have STMP than both G1 and G2; G2 was less positive than G1. IES and HADs were not impacted by type of result. Interactions between gender and age, and result were non-significant for all psychological outcomes. Perceived self-efficacy in coping with results (p=0.015) and knowledge (p=0.04) at T0 was significantly correlated with satisfaction with decision at T1; self efficacy (T0) was also correlated with MICRA total (T1) (p=0.006). Conclusions: Pathway to treatment receipt is less important to advanced cancer patients than actionability. Patients’ self-efficacy to cope with results prior to testing can identify patients vulnerable to distress post-receipt of STMP results who should be offered psychological counseling. Ensuring good knowledge of STMP at consent may avoid decisional regret. [Table: see text]
Ancestry-specific gene expression profiles in TNBC tumors.
Authors: Dean-Colomb Windy Marie , Martini Rachel , Verma Akanksha , White Jason , Elemento Olivier , Davis Melissa , Newman Lisa , Manne Upender , Yates Clayton
Published: May 2020

1547

Background: Due to persistent disparities in breast cancer mortality, there has been a renewed focus on investigating tumor biology. Deeper exploration has exposed distinctions in tumor biology based upon self-reported race and ancestry. The disparities associated with Triple Negative Breast Cancer (TNBC) across the modern African Diaspora suggests that there is a genetic ancestry connection between its aggressive tumor biology and clinical outcomes. Understanding this connection could hold the key to improving clinical outcomes in this group. Methods: We investigated 75 TNBC primary tumors using Self-Reported Race (SRR) groups: African American (AA, n = 42) and European American (EA, n = 33). Using best practices established by TCGA, we analyzed bulk RNA sequencing to measure changes in genome-wide expression levels. We next quantified global ancestry in a novel manner using RNAseq variants using 1000 Genomes as the reference data. We then identified African and European ancestry-associated genes using a logistic regression (adjusted FDR p < 0.05) between quantified ancestry and gene expression levels. Results: We identified > 150 genes associated with quantified African ancestry. We also found using quantified ancestry was a more robust method to screen for differentially expressed genes than SRR. Using an updated TNBC subtyping method, we noted higher incidences of Basal-like 2 tumors in AAs. Pathway analyses indicated several canonical cancer pathways; including, TP53, NFKB1 and AKT, have altered functionality in patients of African descent. For example, TP53-associated genes were activated in TNBC tumors of AA versus EA. This upregulation, rather than loss of function, is suggestive of polymorphic and/or ancestry-specific expression regulation, likely driven by population-private genetic variants. Lastly, we used TCGA data to validate a subset of African ancestry-specific genes that were upregulated in AA patients in our cohort. Specifically, PIM3, ZBTB22 and PPP2R4 each retained significant upregulation, in our cohort, but also TNBC tumors from TCGA (p = 0.0018, 0.023 and 0.022, respectively). Conclusions: Our study has uncovered ancestry-specific gene expression profiles in TNBC tumors. The distinct distribution of TNBC subtypes and altered functional oncologic pathways are evidence that biological underpinnings in TNBC can be driven by shared genetic ancestry. These findings emphasize the need to investigate patient populations of various ancestral origins in order to fully appreciate the molecular diversity in tumor biology for precision of disease management.
Outcomes of Lynch syndrome (LS) patients treated with immune checkpoint inhibitors (ICI).
Authors: Bari Shahla , Kim Richard D. , Wang Xia , Matejcic Marco , Muzaffar Jameel
Published: May 2020

1548

Background: LS is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2 (d-MMR). A minority of LS patients have MMR proficient tumors (p-MMR). ICI therapy has dramatically changed outcome of d-MMR (majority of LS patients. However, data about response to ICI in LS patients, irrespective of their tumor MMR status is scarce. The aim of this study was to evaluate outcomes of ICI therapy in all LS associated Cancer. Methods: This was a retrospective analysis of LS associated cancers treated with one of the 6 ICIs at our center. We also looked at age, sex, microsatellite status, response and survival. Results: Out of 262 LS patients analyzed, 194 had cancer and 22 received ICIs. Among the patients analyzed, the mean age at diagnosis of 1st cancer was 51 yrs. There were 10 females (47%). 10 patients had colorectal (45%), 3 urothelial (14%), 2 renal cell, 2 cholangiocarcinoma and one each of esophageal, ovarian, uterine, glioblastoma multiforme and pancreatic cancer. One patient died from progressive disease after receiving a single dose and was not included in the analysis. 17 patients (80%) received Pembrolizumab, 11 patients were microsatellite unstable (MSI), 3 were microsatellite stable (MSS) while 7 were unknown. 2 patients achieved complete response (CR) (10%), 1 patient had partial response (PR) (5%), 13 had stable disease (62%) while 5 had progressive disease (23%) leading to a disease control rate (DCR) of 76%. Of the 3 known MSS Lynch syndrome patients, 2 did not respond while the 3rd continues to respond at 9 months of therapy. Of the 5 patients who had PD, 2 were MSS, 2 unknown and 1 MSI. Among the 16 patients who responded, 15 of 16 (94%) had sustained response and have not experienced disease progression or relapse. 3 of these patients have been off therapy (1 due to immune related adverse evet) and have had no relapse. One responder progressed after 18 cycles of therapy. The DCR was 71% at 12 months as well as 48 months of follow up. Median progression survival has not been reached. Similarly, median overall survival has not been reached. Conclusions: Our study is the one of the largest reported analysis of LS associated cancer patients treated with ICIs and included LS patients with both MSI and MSS tumors. Though small, our data suggests robust DCR and prolonged responses in Lynch associated MSS tumors treated with ICI. This encouraging response in MSS tumors along with higher response rates in LS associated cancers as compared to non-LS MSI tumors, suggests that there may be additional drivers of response to ICI in LS patients leading to superior responses.
Clinicopathologic features of invasive breast cancer (BC) diagnosed in carriers of germline PALB2, CHEK2 and ATM pathogenic variants.
Authors: Scott Danika , Kingham Kerry , Hodan Rachel , Ma Cindy , Mills Meredith , Ford James M. , Kurian Allison W. , Telli Melinda L.
Published: May 2020

1549

Background: While germline pathogenic variants (PVs) in BRCA1/2 account for a large proportion of hereditary breast cancer (BC), PVs in PALB2, CHEK2 and ATM are increasingly detected. However, the phenotype and clinical features of invasive BC with these PVs have not been fully described. Methods: We identified patients with a PV or likely PV in PALB2, CHEK2 or ATM tested clinically at Stanford between 2014 - 2019 who provided informed consent to be included in a prospective cancer genetics registry. Data on baseline demographics, genetic testing history, and clinicopathologic features of diagnosed BC were collected. For patients with a subsequent diagnosis of metastatic BC, we calculated disease-free interval (DFI). Results: 130 patients met inclusion criteria for analysis: ATM (N=39), CHEK2 (N=58), PALB2 (N=33). Nearly all (98.5%) were women, with 2 male BC in ATM carriers. Non-Hispanic White ethnicity was most common in ATM (64.1%, 95% CI 48.4%-77.3%) and CHEK2 carriers (69.0%, 95% CI 56.1%-79.4%), but comprised only 39.4% (95% CI 24.7%-56.4%) in PALB2 carriers. Asian/Pacific Islander (24.2%, 95% CI 12.6%-41.3%) and Hispanic (30.3%, 95% CI 17.3%-47.5%) ethnicities were enriched among PALB2 mutation carriers. In total, 97.7% learned of their PV status only after a preceding diagnosis of BC and 43.1% were diagnosed with BC at age ≤ 45. Data regarding invasive BC subtypes, incidence of subsequent primary BC, and metastatic recurrence are listed below in the table. Additional data on stage, grade and sites of metastatic spread will be presented. Conclusions: We observed clinically important differences in the spectrum of BC subtypes among carriers of ATM, CHEK2 and PALB2 PVs, in addition to racial/ethnic differences with Asian/Pacific Islander and Hispanic ethnicity enriched among carriers of PALB2 PVs. [Table: see text]