Background
The incidence of cancer in adolescents and young adults (AYAs) aged 15 to 39 years has been increasing steadily.1,2 Although a rare tumor type, sarcomas are seen with relative frequency in AYAs, accounting for approximately 14% of all AYA cancer diagnoses.3 The disproportionate frequency of sarcomas that affect AYAs has been suggested as support for a genetic basis of hereditable conditions in patients with sarcoma, which is also strengthened by the increased risk of second cancers seen in sarcoma survivors.4 Consistent with this, studies have shown a large burden of genetic risk in patients with sarcoma,5,6 including a 2016 study showing that 55% of 1,162 individuals with sarcoma had an excess of pathogenic germline variants.7
Given the known association of sarcomas with several genetic syndromes, including Li-Fraumeni syndrome (LFS),8,9 consideration for genetic counseling is recommended for all AYA patients diagnosed with sarcoma.10,11 Since 2015, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic10 have recommended genetic consultation with possible genetic testing for patients with sarcoma meeting classic LFS criteria12 or Chompret criteria.13,14 Beyond LFS-specific guidelines, the NCCN Guidelines for Soft Tissue Sarcoma review the increased incidence of sarcoma seen in patients with LFS, hereditary nonpolyposis colorectal cancer, neurofibromatosis type 1 (NF1), Carney-Stratakis syndrome, familial adenomatous polyposis (FAP), and hereditary retinoblastoma.15 These guidelines, however, provide no generalized referral strategies for patients with sarcomas and offer only syndrome-specific evaluation considerations. The NCCN Guidelines for AYA Oncology more broadly recommend that a thorough family history be taken, preferably by a genetic counselor11; however, ongoing work has shown that barriers remain to genetic consultation and appropriate cancer risk management.16–18
Given the high prevalence of hereditary cancer predisposition syndromes in AYA patients and patients with sarcoma and the critical importance of genetic consultation in these patients, we sought to understand referral patterns for genetic consultation and subsequent genetic testing in AYA patients with sarcoma at the University of Wisconsin (UW). We sought to evaluate factors influencing genetic consultations in these patients to seek quality improvement opportunities to increase the rate of genetic counseling referrals.
Methods
Medical Record Retrieval
AYA patients with cancer between the ages of 15 and 39 years were identified via electronic health record (EHR) query using age, any cancer diagnosis recorded in hospital or professional billing, and at least 1 visit in 2015 through 2019 at the UW Carbone Cancer Center (UWCCC) or American Family Children’s Hospital (AFCH) with a medical or radiation oncologist. Subsequent physician-led chart review identified patients with sarcoma for study inclusion. Study data were collected via retrospective chart review and managed via a secure institutional database. The study was conducted in accordance with all relevant guidelines and procedures and was approved by the UW Institutional Review Board as a quality improvement project.
Retrospective Chart Review
A retrospective chart review was performed, identifying documentation of discussions regarding genetics, referrals to genetics, genetic consultations, and results of genetic testing. The EHR search function was used to identify discussions regarding genetics by any oncology provider, including physicians, advanced practice providers, and nurses in medical or radiation oncology, and documentation of a referral to genetics. Referrals were also identified by review of EHR orders. Genetic consultation visits were confirmed by review of appointments and consultation notes. Variables hypothesized to affect patient referrals for genetic consultation were identified a priori and included age at diagnosis, sex, race, ethnicity, zip code of patient’s residential location categorized into metropolitan versus nonmetropolitan residential location using Rural-Urban Continuum Codes,19 insurance status, localized versus metastatic cancer at time of diagnosis, receipt of chemotherapy, and documentation of a genetics discussion with an oncology provider.
Statistical Analysis
Patient characteristics were recorded as percentages for categorical variables and as means and standard deviations for continuous variables. Categorical data were assessed using Fisher exact tests, and continuous variables were compared using one-way ANOVA. We used a univariate analysis to identify variables associated with an increased rate of referral for genetic counseling. All P values ≤.05 were considered statistically significant. STATA, version 16 SE (StataCorp LLP) was used to conduct all statistical analyses.
Results
Patient Baseline Characteristics
We identified 87 AYA patients with sarcoma who were seen at least once in 2015 through 2019 at UWCCC or AFCH by a medical or radiation oncologist. Just more than half of the patients were male (54%; n=47), and most identified as White (91%; n=79) and non-Hispanic (97%; n=84). Most patients had health insurance (91%; n=79), with only 19% (n=15) of these having Medicaid or Medicare as their primary health insurance (Table 1).
Patient Characteristics
Table 2 details histologic subtypes seen in the 87 patients, with localized disease noted at the time of diagnosis in most patients (85%; n=74). More than two-thirds of patients (69%; n=60) underwent chemotherapy as part of their treatment regimen, whereas fewer than half of patients (45%; n=39) underwent radiation therapy. Most of these treatments were administered by the adult oncology team at UWCCC (84%; n=73), with only 14 patients (16%) treated at AFCH by the pediatric oncology team.
Sarcoma Histologic Subtypes and Referrals to Genetics
Primary Outcomes
Of the 87 AYA patients with sarcoma identified in our study, only 22% (n=19) had documentation of a discussion about genetics with an oncology provider. There was no statistically significant difference in genetic discussion documentation by adult providers (21%; 15/73) versus pediatric providers (29%; 4/14), nor was there a statistically significant difference in medical versus radiation oncology providers (documentation in 22% [16/74] and 23% [3/13], respectively). Of the 19 patients with documented genetics discussions, 15 were subsequently referred for genetic consultation (79%), which represented only 17% of the total study population (15/87). No patients lacking documentation of a genetics discussion with an oncology provider were referred for a genetics consultation. Of the 4 patients with a documented discussion about genetics but lack of genetics referral, only 1 (25%) with spindle cell sarcoma had documentation of not being referred for genetic consultation because the medical provider believed that the patient’s personal and family history of cancer did not meet requirements for genetic counseling referral. Of the remaining 3 patients, 2 had a lack of follow-up by the referring provider and 1 had an unclear reason for lack of genetics referral.
Of the 15 patients referred to genetics, 60% were seen in consultation (n=9) (Figure 1). Reasons for referral without subsequent consultation were lack of follow-up by patient (4 patients did not return paperwork required to schedule genetic consultation appointment), lack of follow-up by providers (1 was referred, but there were no contact notes from the genetics department), and reasons unknown (n=1). All 9 patients who received consultation (100%) underwent genetic testing, 4 (44%) of whom were identified to have a heritable cancer predisposition syndrome. Syndromes identified included NF1, hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC), FAP, and LFS (Table 2). Upon review of the types of genetic testing performed, 8 patients (89%) had genotype testing and 1 (11%) had karyotype testing to clarify that a translocation identified in her tumor was not germline.
(A) Outcomes of referral for genetic counseling (n=15) and (B) results of genetic testing (n=9).
Abbreviations: FAP, familial adenomatous polyposis; GC, genetic counselor; LFS, Li-Fraumeni syndrome; NF1, neurofibromatosis type 1; PGL/PCC, hereditary paraganglioma-pheochromocytoma syndrome.
Citation: Journal of the National Comprehensive Cancer Network 19, 13; 10.6004/jnccn.2021.7034
(A) Outcomes of referral for genetic counseling (n=15) and (B) results of genetic testing (n=9).
Abbreviations: FAP, familial adenomatous polyposis; GC, genetic counselor; LFS, Li-Fraumeni syndrome; NF1, neurofibromatosis type 1; PGL/PCC, hereditary paraganglioma-pheochromocytoma syndrome.
Citation: Journal of the National Comprehensive Cancer Network 19, 13; 10.6004/jnccn.2021.7034
(A) Outcomes of referral for genetic counseling (n=15) and (B) results of genetic testing (n=9).
Abbreviations: FAP, familial adenomatous polyposis; GC, genetic counselor; LFS, Li-Fraumeni syndrome; NF1, neurofibromatosis type 1; PGL/PCC, hereditary paraganglioma-pheochromocytoma syndrome.
Citation: Journal of the National Comprehensive Cancer Network 19, 13; 10.6004/jnccn.2021.7034
Predictors of Genetic Consultation
Genetic referrals based on patient characteristics are detailed in Table 1. A statistically significant increased likelihood for genetic referral was seen in patients who had a documented genetics discussion with an oncology provider. There was no statistically significant difference in referrals to genetics based on age at diagnosis, sex, race, ethnicity, metropolitan versus nonmetropolitan residence, presence versus absence of insurance, localized versus metastatic cancer at time of diagnosis, and receipt of chemotherapy or radiation therapy. Notably, no patients who identified as Black, Asian, or Hispanic or who lacked health insurance were referred to genetics. Table 2 details genetics referrals by histologic subtype. Review of provider characteristics showed a trend toward increased genetics referrals in patients treated by the adult oncology team (19%; 14/73) versus pediatrics (7%; 1/14), with similar referrals from medical oncology (18%; 13/74) versus radiation oncology providers (15%; 2/13). In univariate analysis (Table 3), no associations were found between referral for genetic counseling and age at diagnosis, sex, metropolitan versus nonmetropolitan residential location, disease stage at diagnosis, and receipt of chemotherapy or radiation therapy.
Univariate Analysis of the Odds of Receiving a Referral for Genetic Counseling
Discussion
Genetic referral and testing are of critical importance for the identification of hereditary cancer predisposition syndromes, with implications for care, including surveillance, screening, and treatment.20–22 In all cancers, identification of such syndromes may inform therapy through identification of an actionable mutation, guide surveillance strategies, or allow application of cancer preventative measures, and it may influence family planning and support testing of at-risk family members.23,24 In sarcomas, such identification is particularly important, given implications for treatment in light of risk of therapy-related malignancies, such as consideration of radiation therapy and anthracycline-based chemotherapy for patients with LFS.25 Despite a high frequency of pathogenic germline variants in sarcomas6,7,26 and in AYAs,5,26 we found that only 17% of AYA patients with sarcoma treated at an NCI-designated Cancer Center had genetic counseling referrals. Because this referral rate is even lower than previously published rates for genetic referrals ranging from 22% to 48% in other age groups and cancers,27–29 we sought to better understand factors influencing genetic consultations in AYA patients with sarcoma.
We found that referral for genetic consultation was linked most strongly to a documented genetics discussion with an oncology provider. Strikingly, despite NCCN Guidelines for AYA Oncology recommending documentation of a thorough family history and consideration for genetic consultation for all AYA patients with cancer,11 only 22% of the 87 AYA patients with sarcoma identified in our study had a documented discussion about genetics with an oncology provider. Other studies have similarly shown that failure of the treating oncologist to refer is the largest obstacle to receiving genetic counseling and/or testing.18,30 Although a variety of reasons for lack of genetics referral from the treating oncologist could be considered, including the absence of a high-risk personal or family history or concerns for insurance coverage, our study findings suggest that this is most often due to underconsideration of genetics by the oncology care team. In fact, only 1 patient in our study had documentation suggesting they were not referred for genetic consultation because the provider believed that the patient’s personal and family history of cancer did not meet requirements for genetic counseling referral. Because genetic consultation is a component of the NCCN Guidelines for AYA Oncology and previous work has shown that higher compliance with NCCN Guidelines is associated with improved outcomes,31–35 the paucity of documentation of genetics discussions in the AYA patients in our study suggests a critical care need for these patients.
Although genetic referral is the first critical step in the process of genetic counseling and testing, there are several other possible areas of care breakdown, which our study also evaluated. Specifically, of the 15 patients referred to genetics, only 60% were seen in consultation, with the most common reason for referral without subsequent consultation being lack of follow-up by the patient. This may suggest possible reluctance for and barriers to genetic consultation among AYA patients. Previous studies have shown that AYAs at increased genetic risk have various challenges regarding the genetic counseling process, including the role of parents/partners/peers, health literacy, mental and emotional health, and available resources.36–40 Other work has shown that, given the potential of genetic testing decisions to affect recurrence and decisions about having children in the future, AYAs can be overwhelmed by genetic counseling considerations,41–43 which may result in the lack of patient follow-up seen in our study and may support ongoing educational initiatives regarding genetic consultation and testing in AYA patients. Workflow modifications should also be considered to avoid required previsit paperwork, which may be a barrier to care particularly for AYAs and was therefore discontinued at UW in 2019.
Despite a limited number of patients, all patients seen by genetics met testing criteria and underwent genetic testing. Supportive of the high frequency of hereditary predisposition cancer syndromes in AYA patients with sarcoma, 44% of patients who underwent genetic testing in our study had a heritable cancer predisposition syndrome identified, with 1 patient each with NF1, PGL/PCC, FAP, and LFS. Although our finding of genetic predisposition of 44% is in agreement with other findings,7,22,44 it is significantly higher than the documented 8% to 9% estimated frequency of germline mutations in cancer-predisposing genes in all AYA patients with cancer.5 Although it is an important finding, the small number of patients in our study limits interpretation of germline mutation frequency in this population. In addition, selection bias cannot be disregarded, because patients who have a more concerning phenotype of family history may be more likely to be referred or to receive follow-up with consultation and testing.
The high burden of genetic risk in AYA patients with sarcoma and the low rates of provider-documented genetics discussion and subsequent consultation highlight the need for more universal genetic counseling in AYA patients with sarcoma. Although family history is an important component of a comprehensive genetics assessment, we argue that oncology providers are not appropriately instructed on how to complete a comprehensive 3-generation pedigree, which is the gold standard family history for determining risk of hereditary genetic predisposition syndromes,29 and that such evaluation is labor-intensive and difficult to implement in a busy oncology practice.45 In addition, hereditary cancer syndromes associated with sarcomas can have a variety of presentations not always captured in a family history of cancer, such as de novo mutations (FAP and LFS), variable expressivity (NF1), or sex-dependent inheritance requiring professional genetic evaluation for appropriate testing options. Given evidence suggesting that family history of cancer may not capture more complex presentations of hereditary cancer syndromes,16,21,46 we suggest that a more universal recommendation should be made for genetic counseling for all AYA patients with sarcoma. Although such a broad recommendation would include a group of extraordinarily heterogeneous tumors with differences in driver aberrations and genetic complexity that affect the risk of hereditary cancer predisposition syndromes, our genetic understanding of sarcomas is limited because the focus has historically been on TP53 testing, with panel testing only more recently used. Even LFS as the most well-known hereditary predisposition syndrome in sarcomas continues to have refinements to clinical and genetic features, and there is emerging consideration of putative genetic causes for predisposition even in rare cases of Kaposi sarcoma, such as through inherited immunodeficiency syndromes.47 Although the syndromes identified in our study were observed in the sarcoma histologic subtypes more commonly associated with genetic predisposition syndromes, we believe universal genetic counseling for all sarcoma subtypes would serve to obtain a more accurate family history for syndrome consideration and further genetic research, establish care for future testing, and provide counseling benefits for this vulnerable population. We believe that such a universal recommendation for genetic counseling for all AYA patients with sarcoma is supported by our study findings and would help to improve genetic counseling use.
A notable limitation of our study includes the retrospective nature of the chart review. Although it is possible that documentation of discussions about genetics in the EHR may not accurately reflect whether providers considered or even engaged patients in a conversation about genetic consultation, we argue that best practice supports documentation of these discussions and that lack of documentation suggests no or limited consideration of genetics in these patients. We also declined to include documentation of family cancer history despite its potential impact on the decision to refer patients for genetic consultation, because documented family history data are frequently pulled from other parts of the EHR and may not represent meaningful documentation by the oncology provider. Small sample size may also limit the generalizability of this study; however, given the relative rarity of sarcoma diagnoses, the sample size in our study is not insignificant. Another important limitation with regard to the frequency of hereditary cancer predisposition syndromes identified in this study is that, although this study reviewed patients seen between 2015 and 2019, some genetic testing was performed before these dates and may have been restricted by available technology and insurance coverage of the time. The genetic tests performed were variable, ranging from single-site gene testing to multisystem panel testing, which limits our interpretation of results, especially related to negative test results. Finally, the low overall numbers of patients referred to genetics in our study may restrict the statistical analysis of variable association with referral to genetics. Considering this, although there was no statistically significant difference in referrals to genetics based on race, ethnicity, or presence or absence of insurance, this may be due to the relatively low numbers of patients referred to genetics. Notably, no patients in our study who identified as Black, Asian, or Hispanic or who lacked health insurance were referred to genetics. This consideration is critical because several studies have reported that minority patients’ needs for genetic discussions and testing are more likely to go unmet,48–50 whereas other studies have not observed different genetic counseling referral rates based on race and ethnicity.51,52 These incongruencies suggest the need for further research to explore the relationship between race, ethnicity, and socioeconomic disparities and genetic resources.
Conclusions
To our knowledge, this is the first study to report factors influencing genetic consultations in AYA patients with sarcoma. Despite the recommendation for consideration for genetic counseling in AYA patients, less than 25% of such patients in our study had a documented discussion about genetics. Almost all patients with such documentation were ultimately referred to genetics, suggesting this initial conversation by a provider is critical to genetics referral and should occur for all AYA patients with sarcoma. Supportive of the need for genetic consultations in these patients, all patients referred to genetics met criteria for genetic testing and 44% of patients who underwent genetic testing were found to have a heritable cancer predisposition syndrome. We believe that these data support consideration of a universal recommendation for genetic counseling in all AYA patients with sarcoma.
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