Rationale for Requested Change: There is a need for non-invasive, broadly accessible, and efficient tests that can screen for a signal shared by multiple cancers simultaneously in at-risk patient populations. Advances in molecular genetics have identified a number of genes associated with inherited susceptibility to breast, ovarian, and pancreatic cancer (e.g., BRCA1/2, PALB2, ATM) and have provided a means of characterizing the specific P/LP variant present in certain individuals and families exhibiting an increased risk for cancer. Under the current standard of care in the US, four cancers (breast, colorectal, cervical, and lung for those at risk) have USPSTF recommended screening. The majority of cancers have no recommended screening making it difficult for those at increased risk to receive consistent required proactive care. Individuals with hereditary cancer syndromes are at risk for the development of multiple different types of cancer (depending on the gene) and screening for all the different types of cancers associated with a given gene may be challenging. Challenges include suboptimal sensitivity and specificity of some screening tests (i.e. TVUS for ovarian cancer in LS and BRCA patients) and challenges in completing multiple different types of cancer screening tests every year.
A targeted methylation-based multi-cancer early detection test (Galleri) is available that can detect a cancer signal and predict cancer signal origin from cfDNA in peripheral blood. This test meets key criteria for a multi-cancer early detection test, including detection of a signal shared by more than 50 cancer types in an elevated risk population, such as those aged 50 or older; preferential detection of aggressive cancers that may minimize overdiagnosis of indolent ones; a low false positive rate of 0.5%; ease of use; and prediction of the cancer signal origin (CSO), tissue or organ associated with the cancer signal, with ~90% accuracy, to help guide diagnostic evaluation. Clinical studies have been published and performance is summarized below.^1-4 MCED testing should be added to other recommended screening procedures.
The Circulating Cell-Free Genome Atlas (CCGA) study was the largest prospective clinical genomics program with over 15,000 participants to discover, develop, and validate a methylation-based cfDNA blood test for multi-cancer early detection.^1-3 GRAIL’s MCED was also studied in another large prospective, interventional, return-of-results study PATHFINDER (N=6,600) in adults > 50 years old without clinical suspicion of cancer.^4 Results of both studies showed specificity >99%, and >88% accuracy in predicting cancer signal origin.^2-4
Ovarian Cancer
Individuals harboring specific pathogenic variants may develop ovarian cancer at an earlier age than the general population and may have a higher lifetime risk of developing ovarian cancer. In the Lynch syndrome population, depending on the specific gene involved, the average age of ovarian cancer development can be in the 40's and the cumulative risk of developing ovarian cancer can be significantly higher than in the general population. According to the NCCN guidelines, BRCA1 variants have an estimated 48.3% cumulative risk of ovarian cancer by age 70, while the cumulative risk by age 70 is 20.0% for carriers of a P/LP BRCA2 variant. Despite these risks, options of ovarian cancer screening in those harboring P/LP are markedly limited and hence there is unmet need for other screening options. Ovarian cancer in general is one of the deadliest cancers in women, in part because it is often found at a late stage. The potential benefit of ovarian cancer screening for those at risk is the chance to find ovarian cancer at an early stage when treatment with curative intent is possible. Non-invasive MCED testing can provide a new screening modality for those at increased risk for ovarian cancer.
In a prospective, case control, longitudinal study in 2823 newly diagnosed cancer participants (cases) and 1254 non-cancer participants (controls), the sensitivity in study participants with ovarian cancer was 83.1% (50.0% for stage I, 80.0% stage II, 87.1% stage III, 94.7% stage IV). Accuracy of Cancer Signal Origin (CSO) was 70.4% in individuals with ovarian cancer. Specificity in non-cancer study participants was 99.5%.^3 When a screening MCED test result is reported as Cancer Signal Detected, immediate diagnostic evaluation based on predicted CSO(s) and NCCN guidance is recommended by the ordering provider, patient primary care provider, or specialist.^4
Pancreatic Cancer
Current NCCN guidelines for pancreatic cancer state that routine screening for pancreatic cancer is generally not recommended for asymptomatic individuals and if recommended, pancreatic cancer screening with cross-sectional imaging or EUS should be performed in experienced, high volume centers. This could potentially limit high-quality pancreatic cancer screening access for some patients. The incidence of pancreatic cancer has markedly increased over the past several decades. In the United States, it ranks as the fourth leading cause of cancer death in men and the third leading cause of cancer death in women. Pancreatic cancer is difficult to detect and diagnose because there may not be noticeable signs and symptoms in the early stages of pancreatic cancer and the pancreas is obscured by other organs in the abdomen and is difficult to visualize clearly on imaging tests. Most symptomatic patients with pancreatic cancer have advanced, incurable disease at diagnosis. Given that outcomes may be better following resection of small invasive cancers, screening and detection of asymptomatic, early, potentially curable pancreatic cancer has the potential to improve outcomes. Non-invasive MCED testing can provide a new screening modality for highly aggressive pancreatic cancer.
In a prospective, case control, longitudinal study in 2823 newly diagnosed cancer participants (cases) and 1254 non-cancer participants (controls), the sensitivity in study participants with pancreatic cancer was 83.7% (61.9% for stage I, 60.0% stage II, 85.7% stage III, 95.9% stage IV).. Accuracy of Cancer Signal Origin (CSO) was 83.9% in individuals with pancreatic cancer. Specificity in non-cancer study participants was 99.5%.^3 When a screening MCED test result is reported as Cancer Signal Detected, immediate diagnostic evaluation based on predicted CSO(s) and NCCN guidance is recommended by the ordering provider, patient primary care provider, or specialist.^4
The sensitivity results for cancer classes included in the Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic guideline are reported in Table 1 and other cancer classes in Table 2.^3
The performance characteristics of this test for noninvasive, broadly accessible early detection of ovarian, pancreatic and other cancers render this test an efficient option for adding to recommended cancer screening tests for individuals at Genetic/Familial High-Risk for Breast, Ovarian, and Pancreatic cancers.
Table 1^3
Cancer Class Overall Sensitivity n,%
Breast 524, 30.5
Ovary 65, 83.1
Pancreas 135, 83.7
Table 2^3
Cancer Class Overall Sensitivity n,%
Anus 22, 81.8
Bladder 23, 34.8
Cervix 25, 80.0
Colon, Rectum 206, 82.0
Esophagus 100, 85.0
Gallbladder 17, 70.6
Head and Neck 105, 85.7
Kidney 99, 18.2
Liver, Bile duct 46, 93.5
Lung 404, 74.8
Lymphoid Leukemia 51, 41.2
Lymphoma 174, 56.3
Melanoma 13, 46.2
Myeloid 10, 20.0
Plasma Cell 47, 72.3
Prostate 420, 11.2
Sarcoma 30, 60.0
Stomach 30, 66.7
Thyroid 14, 0.0
Urothelial 10, 80.0
Uterus 157, 28.0
References:
1. CCGA1: Jamshidi A, Liu MC, Klein EA, et al. Evaluation of cell-free DNA approaches for multi-cancer early detection. Cancer Cell. 2022;40(12):1537-1549.e12. doi: 10.1016/j.ccell.2022.10.022.
2. CCGA2: Liu MC, Oxnard GR, Klein EA, et al. for CCGA Consortium. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31(6):745-759. doi: 10.1016/j.annonc.2020.02.011.
3. CCGA3: Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol. 2021;32(9):1167-1177. doi: 10.1016/j.annonc.2021.05.806.
4. PATHFINDER: Schrag D, Beer TM, McDonnell CH, et al. Blood-based tests for multi-cancer early detection (PATHFINDER): a prospective cohort study. Lancet. 2023;402:1251-1260. doi: 10.1016/S0140-6736(23)01700-2.
