ABSTRACT
Background: Identifying individuals at a higher risk of developing cancer is a major concern for healthcare providers. Cancer predisposition syndromes are the underlying cause of cancer aggregation and young-onset tumors in many families. Germline genetic testing is underused due to lack of access, but Brazilian germline data associated with cancer predisposition syndromes are needed. Methods: Medical records of patients referred for genetic counseling at the Oncogenetics Department at the Hospital Sírio-Libanês (Brasília, DF, Brazil) from July 2017 to January 2021 were reviewed. The clinical features and germline findings were described. Detection rates of germline pathogenic/likely pathogenic variant (P/LPV) carriers were compared between international and Brazilian guidelines for genetic testing. Results: A total of 1,091 individuals from 985 families were included in this study. Most patients (93.5%) had a family history of cancer, including 64% with a family member under 50 with cancer. Sixty-six percent of patients (720/1091) had a personal history of cancer. Young-onset cancers (<50 years old) represented 62% of the patients affected by cancer and 17% had multiple primary cancers. The cohort included patients with 30 different cancer types. Breast cancer was the most prevalent type of cancer (52.6%). Germline testing included multigene panel (89.3%) and family variant testing (8.9%). Approximately 27% (236/879) of the tested patients harbored germline P/LPVs in cancer susceptibility genes. BRCA2, BRCA1, and TP53 were the most frequently reported genes, corresponding to 18.6%, 14.4%, and 13.5% of the positive results, respectively. Genetic testing criteria from international guidelines were more effective in identifying carriers than the Brazilian National Agency of Supplementary Health (ANS) criteria (92% vs. 72%, p<0.001). Forty-six percent of the cancer-unaffected patients who harbored a germline P/LPV (45/98) would not be eligible for genetic testing according to ANS because they did not have a family variant previously identified in a cancer-affected relative. Conclusion: The high detection rate of P/LPVs in the present study is possibly related to the genetic testing approach with multigene panels and cohort's characteristics, represented mainly by individuals with a personal or family history of young-onset cancer. Testing asymptomatic individuals with suspicious family history may also have contributed to a higher detection rate. A significant number of carriers would not have been identified using ANS criteria for genetic testing.
ABSTRACT
OPINION STATEMENT: Current trial design is challenged by the advancement of technologies that have enabled deeper understanding of the molecular drivers of colorectal cancer (CRC). The speed of trial testing and the ability to test larger volumes of promising novel agents in the face of smaller populations identified by molecular profiling are challenges posed to clinical studies. Master protocols that utilize umbrella designs are equipped to deal with potential biomarker and matched treatments simultaneously. Although complex in nature, they increase trial efficiency by utilizing shared screening platforms, test multiple treatments together, and simplify regulatory submission and reporting under a common protocol. Emerging technologies such as circulating tumor DNA (ctDNA) may help speed up adjuvant trials. These studies have been traditionally slow to complete due to low event rates and the high numbers needed to recruit. ctDNA used as a surrogate for minimal residual disease (MRD) and as an early marker of relapse may help counter some of these factors that deter innovation in this setting. Finally, in the era of precision medicine, surgery should not be forgotten as the only potentially curative option to date in metastatic disease. Five-year overall survival following resection of liver metastasis exceeds what can be achieved with chemotherapy alone in selected cases. Surgical advances have lowered morbidity and allow for greater resection volumes and repeated interventions. Although historically challenging, a well-designed randomized surgical intervention trial would greatly facilitate moving single-institution guidelines reported by case series into wider clinical practice.
