We conducted qualitative interviews with patients with cancer and providers to identify gaps in clinical care and highlight care delivery solutions for the return of secondary germline findings.
...Twelve patients and 19 cancer providers from the United States were interviewed between January 2019 and May 2021. Interviews elicited feedback about patient information needs, emotional responses to secondary findings, and recommendations for improving pre-test education.
Patients' responses ranged from gratitude to regret, depending on how much pre-test counseling they received before tumor testing. Providers cited insufficient clinic time as a major barrier to pretest education, favoring online support tools and standardized pre-test education models. Providers had differing perspectives on how pre-test education should be integrated into clinical workflows but agreed that it should include the differences between somatic and germline testing, the likelihood of medically actionable findings, and the possibility of being referred to a genetics provider.
The spectrum of participants' responses to their secondary findings underscores the importance of adequate pre-test discussions before somatic sequencing. Although educational interventions could address patients' information needs and augment traditional pre-test counseling, health care systems, labs, and genetic providers may be called on to play greater roles in pre-test education.
10594 Background: Germline testing can be essential for risk stratification and therapeutic decision making. However, guideline-based testing misses ~50% of people with inherited cancer risk. To ...address this gap, we launched the INSPIRE study, offering universal germline testing (31 non-cancer and 154 cancer genes) to consented patients affected and unaffected with cancer. Methos: In 2020, we initiated a scalable in person/remote consent model without formal pre-test counseling. Consenting patients opted-in for one, both, or neither germline test. Research staff placed orders. Results were reviewed by a genetic counselor. Pathogenic/likely pathogenic (P/LP) and increased risk allele (IRA) results were disclosed by phone and scheduled for a genetic consult. Variant of uncertain significance (VUS)/negative results were disclosed by letter with a genetic consult available on request. Descriptive statistics and chi-squared tests evaluated a priori hypotheses regarding potential factors impacting genetic testing uptake and actionability. Results: We approached 26,920 patients: 22,115 (82%) enrolled, 1,830 (7%) declined, 2,975 (11%) deferred a decision. Consented patients opted for testing for germline cancer (21,871/ 99%), non-cancer (21,731/98%), or neither (160/0.7%). We have returned results to 19,842 patients: mean age 62, 69% female; 72% white, 14% Asian, 5% Black, 9% other; 24% Hispanic. Most patients (15,578) had cancer, 13% with multiple primaries. Among the 19,842 patients, 4,456 (23%) had at least one P/LP/IRA variant; 3,971 (20%) in a cancer risk gene and 589 (3%) in a non-cancer gene. Variant proportion by category was 1,466 (30%) high-penetrance, 847 (18%) moderate-penetrance, 1,127 (23%) low-penetrance, 1,282 (28%) recessive, and 34 (0.7%) preliminary evidence. Penetrance prevalence differed by sex: high penetrance variants were more common in females (33% vs. 27%; p=<0.001) and moderate penetrance variants were more common in males (21% vs. 17%; p=0.003). 16,883 (85%) individuals carry at least one VUS. Conclusions: A scalable model to increase germline genetic testing among unselected cancer and unaffected patients across >20 sites was highly feasible. A significant proportion of patients had actionable findings in cancer and non-cancer genes. Next steps include analyses to establish variant prevalence across groups, a longitudinal assessment of psychological outcomes and an evaluation of the impact of result disclosure on cost, patient care, and outcomes.
10604
Background: Most individuals with Hereditary Breast-Ovarian Cancer Syndrome (HBOC) are unaware of their risk. Criteria-based testing will not close this gap as it fails to identify ~50% of ...mutation carriers. Universal germline testing (GT) in oncology stands to identify more mutation carriers and advance cancer control. However, the clinical utility of universal germline testing is unknown. Methods: The City of Hope INSPIRE study offers all consented patients GT for cancer susceptibility (155 genes) and actionable disorders (59 genes). We used an informatics approach to evaluate healthcare utilization for patients found to have BRCA1/ BRCA2 mutations. We queried codified data in our electronic data warehouse before and after GT (post testing interval: 1-29 months). We binned care as possibly related/ not related to HBOC based on NCCN guidelines. Results: Of 10,814 patients who had GT, 217 (2%) had a pathogenic/ likely pathogenic mutation in either BRCA1 or BRCA 2. The demographic distribution of mutation carriers was: white (n = 162, 75%), Asian (n = 28, 13%), Hispanic (n = 65, 30%); female (n = 184, 85%); the mean age was 54 yrs. Eighty-four percent (n = 182) had cancer, including 64% with cancers associated with HBOC (breast 40%, ovarian 13%, pancreatic 3%, 5% prostate, and 0.5% melanoma) and 18% with cancers that are not associated with HBOC. Eighty-three percent of patients had procedures, imaging, and/or therapy potentially related to the BRCA mutation. Eighty-six percent of cancer patients had potentially related care. As expected, use of breast MRI, mammography, MRCP, mastectomy, and bilateral salpingo-oophorectomy (BSO) occurred both before and after testing, with most utilization occurring prior to GT and likely related to cancer staging and treatment. The exception was MRCP which occurred more often following GT (0.6% before vs 1.2% after). Fifty-one (28%) cancer patients received PARP inhibitors. In the unaffected cohort, 67% of patients received possibly related care. Use of mammography was higher prior to GT (7% vs 2%). Consistent with the fact that some unaffected patients were likely known mutation carriers prior to consent, mastectomy was higher prior to GT (5% vs 0%) and BSO was equivalent before and after GT (1.8%). Use of breast MRI (9% vs 15%), MRCP (1.8% vs 3%) and transvaginal US (5% vs 7%) were all higher after GT. Conclusions: We found high levels of relevant healthcare utilization for BRCA mutation carriers in the context of universal GT. However, this initial informatics approach is limited because key information on prior GT and motivations for surgery (e.g., therapeutic vs prophylactic mastectomy) are not adequately captured in codified data. Codified EHR queries will need to be augmented by text mining and/or manual chart review to fully capture care and assess the clinical utility of system-wide genetic care delivery interventions.
10603
Background: Most individuals with Lynch syndrome (LS) are unaware of their risk. Criteria-based testing will not close this gap as it fails to identify ~50% of mutation carriers. Universal ...germline testing (GT) for in oncology stands to identify more mutation carriers and advance cancer control. However, the clinical utility of universal germline testing is unknown. Methods: The enterprise-wide City of Hope INSPIRE study offers all consented patients GT for cancer susceptibility (155 genes) and actionable disorders (59 genes). We used an informatics approach to evaluate healthcare utilization for patients found to have MLH1, MSH2, MSH6, PMS2 or EPCAM mutations. We queried codified data elements in our electronic data warehouse before and after GT (post testing interval: 1-29 months). We binned care as possibly related/ not related to HBOC based on NCCN guidelines. Results: Of 10,814 patients who had GT, 80 (0.74%) had a pathogenic/ likely pathogenic mutation in either MLH1, MSH2, MSH6, PMS2 or a 3’ deletion of EPCAM. The demographic distribution of LS patients was: white (n = 51, 64%), Asian (n = 13, 16%), Hispanic (n = 19; 24%); female (n = 51, 64%); the mean age was 54 yrs. Eighty-six percent (n = 69) had cancer, including 45% with cancers associated with LS (colorectal 17%, endometrial 7%, ovarian 6%, esophageal/stomach 5%, bladder/urinary tract 5%, and prostate 5%) and 41% with cancers that are not associated with LS. Fifty-two percent of all LS patients had procedures, imaging, and/or therapy potentially related to their LS diagnosis. As expected, utilization of colonoscopy, EGD, MRCP/EUS, transvaginal ultrasound, and hysterectomy with bilateral salpingo-oophorectomy (HBSO) occurred both before and after testing for the cancer cohort, with the majority of utilization occurring after testing likely related to their Lynch syndrome diagnosis. Twelve (17%) cancer patients with Lynch syndrome received Immune Checkpoint Inhibitor therapies. In the unaffected cohort, rates of utilization were higher prior to testing for transvaginal ultrasound possibly because 2% underwent a HBSO after their diagnosis and no longer required endometrial surveillance. Rates of colonoscopy, EGD, and HBSO were all higher after GT. Conclusions: We found high levels of relevant healthcare utilization for Lynch syndrome gene mutation carriers in the context of universal GT. However, this initial informatics approach is limited because key information on prior GT and motivations for surgery (e.g., therapeutic vs prophylactic HBSO) are not adequately captured in codified data. Codified EHR queries will need to be augmented by text mining and/or manual chart review to fully capture care and assess the clinical utility of system-wide genetic care delivery interventions.
10600
Background: Germline testing (GT) use is on the rise given testing implications for identifying cancer susceptibility and therapeutically actionable alterations. Scalable models of care that ...emphasize post-test, as opposed to pre-test, genetic counseling are needed to meet demand. However, little is known about the psychological impact (PI) of test result disclosure in such models. Methods: The enterprise-wide City of Hope INSPIRE study offers all consented patients GT for cancer susceptibility (155 genes) and actionable disorders (59 genes). In 2022, we surveyed a sub-set of English-speaking participants ~1 month following test result disclosure. We evaluated PI using the Feelings about Genomic Testing Results (FACToR) measure (distress/ uncertainty subscales 0-12; positive subscale 0-16) and explored associations between patient characteristics, GT results and PI. Results: Of 1000 patients surveyed, 615 completed at least one of the FACToR questions. Participants were mostly white (n=463, 75%) or Asian (n=12.52, 13%) and female (n=419, 68%) with a mean age of 62 yrs. 357 (61%) had a cancer diagnosis and most opted for both GT panels (97%). Eighteen percent had a pathogenic/likely pathogenic variant (PV/LPV) in an autosomal dominant condition, 8% were carriers for an autosomal recessive condition, 53% had at least one variant of unknown significance (VUS) and 21% had negative results. Most patients (n=583, 95%) had low levels of distress with a mean score of 1.67 (SD 2.31). Out of the 30 (5%) patients with higher levels of distress (score >7), results were similar for patients with and without cancer (5% and 4% respectively). Of the 30 patients with higher distress, 67% had a P/LPV variant (13 with and 7 without cancer). Patients also had low levels of uncertainty with a mean score of 2.22 (SD 2.61) and 93% (n=569) scored <7. For those who scored higher on uncertainty (n=44, 7%), most people had cancer and a VUS (n=16, 36%), followed by cancer and LPV/PV (n=10, 23%) followed by patient without cancer with a VUS (n=6, 14%). Finally, 56% (n=44) had high positivity scores (9-16); mean 9.18 (SD 4.31). Fifty-six percent of patients felt a “good/great deal” happy about their GT and 54% were a good/great deal relieved about their results. Conclusions: After implementing an enterprise-wide germline testing program with an emphasis on robust post-test genetic counseling, we found very little evidence of post-disclosure distress or uncertainty. Similar to prior studies, we found that a small proportion of patients may be more vulnerable to negative PI. More work is needed to prospectively identify at risk patients to provide support to this population as we continue to develop safe, effective, and scalable models of care.
Background
The American Society of Breast Surgeons recommends genetic testing (GT) for all women with breast cancer (BC), but implementation and uptake of GT has not been well-described.
Methods
A ...retrospective chart review was performed for newly diagnosed BC patients or patients with a newly identified recurrence of BC seen in a multidisciplinary clinic (MDBC) who were offered genetic counseling (GC) and GT.
Results
The 138 women attending the MDBC had a median age of 54 years and comprised non-Hispanic whites (46%), Asians (28%), Hispanics (17%), blacks (4%), and other (5%). Of the 105 (76%) patients without prior GT, 100 (95%) accepted GC, with 93 (93%) of these 100 patients undergoing GT. The patients meeting the National Comprehensive Cancer Network (NCCN) guidelines for GT were more likely to undergo GT. Testing was performed with a 67- to 84-gene panel, together with an 8- to 9-gene STAT panel if needed. Among 120 patients with reports available, including 33 patients previously tested, 15 (12%) were positive (1
BLM
, 1
BRCA1
, 3
BRCA2
, 1
BRIP1
, 1
CFTR
, 1
CHEK2
, 1
MUTYH
, 1
PALB2
, 1
PRSS1
, 1
RAD50
, 1
RET,
and 2
TP53
), 44 (37%) were negative, and 61 (51%) had an uncertain variant. The median time to STAT results (
n
= 50) was 8 days. The STAT results were available before surgery for 47 (98%) of the 48 STAT patients undergoing surgery.
Conclusions
New BC patients attending the MDBC demonstrated high rates of acceptance of GC and GT. The combination of GC and GT can offer timely information critical to patient risk assessment and treatment planning.
Abstract Background: Because African American and Latina women have been less likely to undergo germline testing, it has been difficult to determine the prevalence of hereditary breast and ovarian ...cancer predisposition in these populations. Here we report the prevalence of BRCA1/2 mutation in patients with a breast cancer diagnosis from City of Hope’s (COH) INSPIRE (Implementing Next-generation Sequencing for Precision Intervention and Risk Evaluation) study. Methods: Patients with a history of any stage breast cancer (stage 0-IV), who were seen by a City of Hope physician at the Duarte or Upland campuses, were approached by a clinical research coordinator for participation in an institutional tissue biorepository project. Demographic information included age, race and ethnicity. Patients consent for this IRB-approved study to store tumor specimens for future research use and Invitae germline testing for 155 predisposition genes which is performed at no cost to the patient. Results: From 7/9/20 until 4/2023, 2413 women consented for participation and underwent germline testing. Mutations in BRCA1 were identified in 53 and BRCA2 in 65. Table 1 summarizes the prevalence of BRCA1/2 mutations according to race and ethnicity. Pathogenic variants in BRCA1 were identified in 22/742 (3.0%) of Hispanic women compared to 16/1552 (1.7%) non-Hispanics (p=0.046). BRCA2 mutations were comparable 16/742 (2.2%) Hispanics and 47/1505 (3%) non-Hispanics. Hispanic women with breast cancer were 2.49 times as likely as non-Hispanics to carry a pathogenic germline BRCA1 mutations than BRCA2 (p=0.026) Conclusion: The prevalence of BRCA1/2 mutations in the African American and Latina population is higher than what was observed in White women. These data provide additional support for the recommendation to perform germline testing in all women with breast cancer, regardless of race or ethnicity Prevalence of BRCA 1 and 2 mutations by Self-Reported Race and Ethnicity # Tested BRCA1 BRCA2 BRCA1 or 2 VUS/Negative Race Native American 15 0 1 (6.7%) 1 (6.7%) 14 (93.3%) Pacific Islander 8 0 0 0 8 (100%) Asian 367 5 (1.4%) 11 (3%) 16 (4.4%) 351 (95.6%) Black 136 7 (5.1%) 4 (2.9%) 11 (8.1%) 125 (91.9%) White 1675 37 (2.2%) 44 (2.6%) 81 (4.8%) 1594 (95.2%) Other 86 1 (1.2%) 4 (4.7%) 4* (4.7%) 82 (95.3%) Unknown 126 3 (2.4%) 1 (0.8%) 5 (3.2% 122 (96.8%) TOTAL 2413 53 (2.2%) 65 (2.7%) 117 (4.8%) 2296 (95.2%) Ethnicity Hispanic 742 22(3%) 16 (2.2%) 37* (5%) 705(95%) Non-Hispanic 1552 26(1.7%) 47(3%) 73(4.7%) 1479 (95.3%) Unknown 119 53(2.2%) 2(1.7%) 7(5.9%) 112(94.1%) TOTAL 2413 53(2.2%) 65(2.7%) 7(5.9%) 112(94.2%) * Patient had both BRCA1 and BRCA2 mutations Citation Format: Joanne Mortimer, Sydney Lindsey, Ilana Solomon, Wai Park, Duveen Sturgeon, Kathleen Blazer, Stacy Gray, Joseph Bonner, Xiaoyu Xia, Stephen Gruber. Prevalence of BRCA1/2 mutations in an underrepresented population of women with breast cancer: Observations from the City of Hope INSPIRE study abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-08-04.
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e14006
Background: Next generation sequencing (NGS) allows for reliable, comprehensive and cost-effective identification of clinically actionable genetic and genomic alterations. The ...increasing adoption of NGS in clinical oncology has increased our ability to identify germline alterations predisposing to cancer development as well as somatic changes enabling prescription of individualized cancer treatment and enhanced clinical trial participation. Here we summarize implementation of an NGS-based precision medicine initiative involving oncology patients from a single institution cancer center. Methods: IRB-approved NGS matched whole exome (WES) germline and solid tumor somatic tumor sequencing together with somatic tumor RNA sequencing (RNA-seq) were performed using germline DNA extracted from peripheral blood lymphocytes and nucleic acids for tumor DNA and RNA sequencing obtained from formalin-fixed, paraffin-embedded tumor specimens. Results of sequencing and analyses were presented to a multi-disciplinary tumor board to establish recommendations for management of germline pathogenic variation, therapeutic drug matching, clinical trials eligibility and molecularly informed patient prognosis. Results: A total of 1,005 patients completed sequencing. Germline and somatic WES exceeded 100X and 250X mean target coverage, respectively; somatic RNA-seq exceeded 200 million mean reads. Patients ranged in age from 17 to 90 years. The study cohort comprised comparable numbers of female (51%) and male (49%) patients. Ethnicities and races were broadly represented with 22% of participants identifying as Hispanic, 14% as Asian, 4% as Black, 55% as Non-Hispanic White and 5% as other. The most common solid tumor histological classification was colorectal (18%), followed by breast (16%), prostate (7%), head and neck (7%), sarcoma (7%), ovarian (5%), melanoma (4%) and lung (3%). Bioinformatic analyses and precision medicine tumor board review established that 12% of patients harbored a germline pathogenic variant and 43% carried clinically actionable genetic/genomic alterations; a majority of patients met molecular requirements for participation in a clinical trial. Conclusions: This study confirms the feasibility and utility of clinical NGS and precision medicine tumor board review in clinical oncology to identify germline genetic pathology, deliver personalized cancer therapeutics, increase clinical trial enrollment and clarify diagnosis and prognosis.
Research suggests variants of uncertain significance (VUSs) present a variety of challenges for genetic counselors (GCs), nongenetics clinicians, and patients. Multigene cancer panels reveal more ...VUSs than single gene testing as a result of the increase in the number of genes being tested. This study surveyed 87 clinical cancer GCs involved with direct patient care and 19 laboratory GCs who provide guidance to clinicians regarding genetic test results about their attitudes on various options for the reporting of VUSs by laboratories for broad multigene cancer panels. Independent samples t‐tests were utilized to compare the two groups. Based on a six‐point Likert‐type scale (1 = Strongly Disagree to 6 = Strongly Agree), clinical cancer GCs (M = 5.4; SD = 0.8) and laboratory GCs (M = 5.2; SD = 0.9) agreed overall that VUSs should be reported (p = 0.44; Cohen's d = 0.21). When asked about specific reporting options, both clinical cancer GCs (M = 1.9; SD = 1.1) and laboratory GCs (M = 2.1; SD = 1.4) disagreed that VUSs should be reported only for genes related to the indication for testing (p = 0.50; Cohen's d = 0.17). Overall, most GCs felt clinicians should not choose whether VUSs should be reported on genetic test results, with clinical cancer GCs (M = 1.9; SD = 1.3) feeling more strongly against it than laboratory GCs (M = 3.1; SD = 1.4; p = 0.002; Cohen's d = 0.88). Generally, GCs were more in favor of VUSs not being reported for population‐based screening, with laboratory GCs (M = 4.7; SD = 0.8) agreeing more with that practice than clinical cancer GCs (M = 3.7; SD = 1.4; p = 0.001; Cohen's d = 0.80). Both clinical cancer GCs (M = 4.1; SD = 1.2) and laboratory GCs (M = 3.9; SD = 1.2) agreed additional guidelines on how to approach VUSs in clinical practice should be developed (p = 0.54; Cohen's d = 0.17). While most GCs supported the reporting of VUSs overall, our analyses suggest clinical cancer and laboratory GCs may have different attitudes toward specific VUS‐related reporting options. Further research is needed to elucidate GC preferences to help inform best practices for the reporting of VUSs. The development of additional standardized guidelines on how to approach VUSs would further support clinical practice.
