Garber, Judy E.

AbstractGermline genetic testing for inherited cancer risk is increasingly being performed with multigene panel testing with MUTYH often included on colorectal cancer‐ and polyposis‐focused panels, as well as on broader pan‐cancer panels. With up to 1%–2% of the general population being monoallelic MUTYH carriers, pathogenic/likely pathogenic (P/LP) variants in MUTYH are one of the most common findings on multigene cancer panels. However, little is known about patient experience and understanding of monoallelic MUTYH P/LP variants, nor whether such findings influence medical management recommendations and familial communication, which this study aims to better understand. Monoallelic P/LP MUTYH carriers were recruited from the Prospective Registry of Multiplex Testing (PROMPT) and completed a cross‐sectional self‐report survey on sociodemographic characteristics, medical and family history, experiences with MUTYH genetic testing, genetics and MUTYH knowledge, perceived cancer risk, and familial communication. Of 115 eligible PROMPT participants, 49 (43%) completed the survey who were primarily female (94%), white (96%), had a history of cancer (61%), and a median age of 51.4 years. Most participants (61%) reported satisfaction with how their healthcare provider managed their genetic test result and care, and 65% of survey participants reported their provider recommended colonoscopy based on their genetic test results. Participants' responses also reflected variable levels of knowledge regarding cancer risks and screening recommendations for MUTYH carriers. The majority (98%) of participants shared their genetic test results with at least some of their relatives; however, only 13% of eligible relatives reportedly underwent cascade testing. Taken together, this study provides needed insight into the overall experiences of monoallelic MUTYH carriers and highlights numerous areas for improvement in clinician education, communication, and management of these individuals.

Abstract Background: Roughly 7–10% of patients with pancreatic ductal adenocarcinoma (PDAC) have a deleterious germline variant. Although identification of germline variants in family members has implications for cancer surveillance and can lead to early cancer detection and interception for PDAC, as well as other cancers, cascade genetic testing rates are low. The GENetic Education, Risk Assessment and TEsting (GENERATE) study evaluates novel methods of providing genetic education and testing for individuals at risk for hereditary PDAC. Methods: Eligible participants had: (1) a first- or second-degree relative with a diagnosis of PDAC and a known familial germline variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 (Known Familial Mutation (KFM)), (2) or were first-degree relatives of PDAC patients (no KFM). Participants were recruited through six academic centers, patient advocacy organizations and online outreach. Enrollment occurred through the study website (www.GENERATEstudy.org). All study participation, including genetic testing via a at home saliva sample kit, was done remotely. Participants were cluster randomized at the family level into one of two arms. Arm 1 (Doxy.me plus Color Genomics) included remote genetic education and testing through a video-based telemedicine platform (Doxy.me) and physician-mediated testing through Color Genomics. Arm 2 included remote genetic education and testing through Color Genomics only. Results: Between 5/8/2019–6/01/2021, 423 families were randomized, comprising 595 participants. Recruitment occurred through patient invitation via healthcare providers (n=128, 21.5%), family members (n=271, 45.5%), friends, advocacy groups, and online outreach (n=223, 37.5%). Participants were referred from the six GENERATE academic centers (n=270, 45.4%) and other institutions (n=325, 54.6%). Study participants were 52.5 years on average, primarily identified as White (n=577, 97%) and from the Northeast (n=184, 30.9%), Midwest (n=154, 25.9%), South (n=158, 26.6%) and West (n=99, 16.6%). Participants were randomized into each arm (n=296 Doxy.me plus Color Genomics; n=299 Color Genomics only). To date, 527 (88.6%) participants have ordered genetic testing. The uptake of genetic testing was 253/296 (85.5%) in the Doxy.me plus Color Genomics arm and 274/299 (91.6%) in the Color Genomics only arm (p=0.049, generalized mixed-effects model). A total of 82 PDAC associated pathogenic variants were identified. The most frequently detected variants were BRCA2 (n=32), ATM (n=25) and PALB2 (n=6). Additionally, 13 non-PDAC associated pathogenic variants and 20 low penetrance variants were detected. Conclusions: Remote methods of genetic education and testing are successful alternatives to traditional cascade testing, with genetic testing rates nearly 90%. Participant follow up will assess if satisfaction with decision making, cancer-risk distress, knowledge gained, family communication, and uptake of surveillance were impacted by the mode of delivery of pre-test genetic education. Citation Format: Nicolette J. Rodriguez, Constance S. Furniss, Matthew B. Yurgelun, Chinedu Ukaegbu, Pamela E. Constantinou, Alison N. Schwartz, Jill Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott Nelson, Sydney Okumura, Sherman Law, Alicia Y. Zhou, Tara B. Coffin, Hajime Uno, Allyson Ocean, Florencia McAllister, Andrew M. Lowy, Scott M. Lippman, Alison P. Klein, Lisa Madlensky, Gloria M. Petersen, Judy E. Garber, Michael G. Goggins, Anirban Maitra, Sapna Syngal. Comparison of novel healthcare delivery models on the uptake of genetic education and testing in families with a history of pancreatic cancer: The GENetic Education, Risk Assessment and TEsting (GENERATE) study [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-013.

Abstract Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. Prevention Relevance: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.

Abstract Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and toxicity limits use of these agents. Vitamin D is a potential prevention therapy for both ER+ and ER− disease and is safe with few side effects. This study evaluates the effect of 1-year of vitamin D supplementation on mammographic density (MD), a biomarker of breast cancer risk in a multicenter randomized controlled trial. Premenopausal women with ≥25% MD and no history of cancer were randomly assigned to 2,000 international units (IU) of vitamin D or placebo orally daily for 1 year. Change in percent MD was evaluated using Cumulus software after all participants completed treatment. Three hundred women enrolled between January 2011 and December 2013 with a mean age of 43 and diverse ethnicity [14% Hispanic, 12% African American (AA)]. Supplementation significantly increased vitamin D levels compared with placebo (14.5 ng/mL vs. −1.6 ng/mL; P < 0.0001) with all participants on the vitamin D arm achieving vitamin D sufficiency at 12 months. Vitamin D was safe and well tolerated. After adjustment for baseline MD, the mean between-arm difference (vitamin D vs. placebo) at 1 year was −0.75 (−0.26, 1.76; P = 0.56). A greater effect was seen for women with ≥50% MD and AA women, although neither reached significance. This randomized controlled trial demonstrated significant improvement in vitamin D levels with 2,000 IU for 1 year, with 100% of supplemented women achieving sufficiency. However, a null effect was seen regarding change in MD for premenopausal women (the primary outcome of the study). Prevention Relevance: Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and are underutilized due to toxicity and side effects. Vitamin D is a potential prevention therapy for both ER+ and ER− disease and is safe with few side effects.

Abstract Purpose: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors—a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. Patients and Methods: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. Results: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35–49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3–4 adverse events related to low-dose tamoxifen. Conclusions: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

PURPOSE Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown. PATIENTS AND METHODS We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]). RESULTS Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [ P = .02] and 7.1% v 4.2% [ P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non–breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC. CONCLUSION Mutation rates are at least 7% in all patients with BRCA1/2 mutation–negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.

Abstract Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li–Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G&gt;C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G&gt;C probands and one c.1000G&gt;A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G&gt;C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G&gt;C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. Significance: TP53 c.1000C&gt;G;p.G334R is a pathogenic, Ashkenazi Jewish–predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.

e13680 Background: Multiplex genetic testing (MGT) simultaneously analyzes multiple cancer susceptibility genes and can reveal genetic variants of uncertain significance (VUS) that have unclear associations with cancer risks. Little is known about how people are prepared for receiving VUS results from MGT, or whether their emotional reactions differ based on the levels of cancer risk to which they may be susceptible. Methods: We recruited participants from the online Prospective Registry of Multiplex Testing (PROMPT). Those with only a VUS in a cancer predisposition gene completed a survey including measures of their MGT experience, distress (range 0-30; α = .87), uncertainty (0-45; α = .83), and positive experiences (0-20; α = .75). We used generalized linear modeling to examine how demographics, awareness of the possibility of VUS before testing, and level of cancer risks associated with their VUS gene were related to emotional outcomes. Results: Data were available from 661 individuals (40% response rate, 95% female, 90% white, 78% college graduate, 69% cancer history, age 23-93) with VUS in a gene of high risk (47%), moderate/low risk (35%) or limited evidence of risk (18%). Among the sample, 80.8% reported ever receiving cancer genetic counseling, and only 50.8% reported being aware of the possibility of VUS when deciding about testing. Participants reported low current distress ( M± SD= 3.25±5.19), uncertainty (9.18±8.35) and positive experiences (7.83±5.98). Distress was associated with younger age, less family cancer history, and being unaware of the possibility of VUS before testing; distress was also higher among those with VUS in a gene of high risk than those with VUS in a gene of moderate/low risk or limited evidence of risk ( ps≤.023). Uncertainty was associated with younger age, non-white race, less education, and being unaware of the possibility of VUS; uncertainty was also higher among those with VUS in a gene of high risk than those with VUS in a gene with limited evidence of risk ( ps≤.05). Fewer positive experiences were associated with more education and more family cancer history; those with VUS in a gene of high risk had fewer positive experiences than those with VUS in a gene with limited evidence of risk ( ps≤.03). Conclusions: Many individuals undergoing MGT may not fully understand the prospect of receiving VUS. Clinicians should consider patients’ background, preparation, and level of cancer risk to which they are potentially susceptible, as these factors may affect their emotional adaptation.

1508 Background: With the expansion of multigene panel testing for cancer susceptibility, increasing numbers of patients are identified with pathogenic/likely pathogenic variants (P/LP V) in genes which do not have a clearly actionable increased risk of ovarian cancer (OC) (lifetime risk of OC >5%). However, there is concern that patients and/or providers may ascribe OC risk to such genetic findings with the potential for unnecessary oophorectomy (ooph). Methods: The Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals with a genetic alteration detected on multiplex panel testing for cancer susceptibility. Participants self-enroll and complete baseline and annual follow-up questionnaires. PROMPT has enrolled 7388 participants (6936; 93.9% women) since September 2014. Results: 1566 women in the PROMPT registry reported ooph, the indications for which were reported as either cancer treatment (n=481, 30.7%) or benign disease (n=432, 27.6%). An additional 186 (12.8%) reported PV in genes associated with lifetime OC risk >5% ( BRCA1, BRCA2, RAD51C, RAD51D, BRIP, or Lynch syndrome genes). The remaining 467 did not have guideline based indications for ooph due to OC risk and are described further here. 92 (19.7%) had a variant of uncertain significance (VUS) in genes associated with OC, 241 (51.6%) had a personal history of breast cancer (BC) and no VUS in OC genes, and 119 (25.5%) had no personal history of BC and no VUS in OC genes. The majority of women had no family history (FH) of OC in first or second degree relatives (Table). Most ooph occurred prior to age 50. Of the 405 women with CHEK2 P/LP, 11.4% reported ooph (59% under age 50 when age known), as did 13.2% (of 228) with CHEK2 VUS, 8.8% (of 261) with ATM P/LP (66.7% under age 50), and 8.3% (of 387) with ATM VUS. In addition, of the 184 women with PALB2 P/LP, 14.1% reported ooph (35.3% under age 50) as did 11.6% (of 198) with PALB2 VUS. Of those who reported provider discussions, 47.2% stated “my provider recommended this” (including >60% in the OC gene VUS group) and an additional 25.2% stated “my provider presented this as an option, but not a requirement”. In those with no FH of OC, 45.8% stated that their provider recommended ooph. Conclusions: 10-15% of women with PV/VUS in genes not associated with a high risk of OC reported ooph without a clear indication. [Table: see text]