Novel Blood-Based Early Cancer Detection: Diagnostics in Development

Abstract

Cancer affects millions of Americans, and the number of cases is steadily rising. The increase in diagnosis of cancer cases comes with an associated increase in personal and economic burden. Earlier detection can improve treatment outcomes and may reduce the burden of cancer. Screening for cervical cancer is a good example of the potential of effective screening methods to dramatically reduce the morbidity and mortality associated with cancer. However, many current screening methods have high false-positive rates, increasing the concern for overdiagnosis and overtreatment. Blood-based tests capable of detecting multiple types of cancer represent an emerging approach to early cancer detection. Although there are several single-cancer detection tests in development, multicancer screening tests have greater potential to allow for widespread screening in the general population. Three multicancer screening tests are being validated in ongoing clinical trials, including the CancerSEEK assay, the Galleri test, and the PanSeer assay, all of which show high specificity in preliminary findings. Further validation is required before multicancer detection tests are incorporated into general population cancer screening.

Am J Manag Care. 2020;26(suppl 14):S292-299. https://doi.org/10.37765/ajmc.2020.88533

Introduction

Cancer is the primary cause of death in those younger than 80 years and is the second leading cause of death in the United States.^1,2 Nearly 1700 people are expected to die from cancer each day in the United States in 2020.³ The American Cancer Society (ACS) estimates the number of new cancer cases and cancer deaths in the United States each year, and the 2020 projections include just over 1.8 million new cancer cases and just over 600,000 cancer deaths.¹ The Centers for Disease Control and Prevention (CDC) provided similar estimations for new cancer cases and cancer deaths.⁴ The efforts to increase awareness of cancer, including prevention and screening, contributed to the decrease in the cancer mortality rate in the United States over the past 20 years.^1,5 Notably, survival decreases significantly when cancer is detected at later stages. Even accounting for lead time bias (which occurs when patients live longer due to earlier detection) and length bias (which occurs when early detection tests preferentially detect slower growing cancers, creating a false impression of longer survival) inherent to earlier detection of disease, there remains a significant opportunity to reduce the burden of cancer with effective early detection. The true benefit of early detection is only realized if effective early treatment produces better results for patients and must not be confused with these biases. There are currently no general population screening recommendations for many types of cancer, which reinforces the need to develop reliable methods for early detection for all types of cancer.⁵

Cancer Burden

According to the National Cancer Institute, the most common cancer in the United States is cancer of the breast, followed by lung.⁶ Table 1 depicts a list of the top 10 cancers in the United States along with an estimate of new cases and deaths for these cancers in 2020.⁶

The number of cancer cases is expected to increase in 2020, with the distribution of increases across specific cancers varied between men and women. According to the CDC, melanoma is expected to increase in White men and women.⁴ It is also estimated that males will experience an increase in prostate, kidney, liver, and bladder cancers, whereas an increase in lung, breast, uterine, and thyroid cancers is expected in females.⁴ Of the cancer cases expected to rise, only lung and breast have current screening recommendations for the general population.⁷ Although some screening methods are available for several other types of cancers, including ovarian, prostate, testicular, pancreatic, and thyroid, screening is not recommended in the general population unless there is presence of specific risk factors.^7,8 The cancer mortality rate has steadily dropped since the 1990s, which is mostly attributed to a decline in death from lung, prostate, breast, and colorectal cancers; mortality rates per 100,000 people are expected to continue to decrease in these cancers in 2020, as well as with cancer of the oral cavity, pharynx, and cervix.⁴ Prevention strategies, such as human papillomavirus (HPV) vaccination, earlier detection of some cancers, declining tobacco use, and improvements in treatment of both early-stage and advanced cancers, may be contributing factors to the decline in cancer-related mortality.

Cancer detection at later stages may be associated with a reduction in survival. For example, when renal carcinoma is detected while still localized in the kidney, the 5-year survival is 93%, but that survival estimate decreases to 12% when the cancer has metastasized.⁹ Similarly, the 5-year survival of female breast cancer drops from 99% when detected locally, to 27% when the cancer has metastasized.⁹ In fact, most types of cancer have a 5-year survival rate of less than 30% when detected after the cancer metastasized.⁹ The potential for improvements in early detection of cancer to alter mortality was examined in a retrospective analysis using data from the Surveillance, Epidemiology, and End Results (SEER) program.¹⁰ The population included men and women aged 50 to 79 years diagnosed with 17 different cancer types at various stages. Of the cancers diagnosed at the advanced or metastatic stage, lung, colorectal, non-Hodgkin lymphoma, pancreatic, and oral cavity cancers were most common. Lung and colorectal cancers specifically were the largest contributors to absolute cancer-related deaths when diagnosed at stage IV; however, overall cancer burden was increased by any cancer diagnosed at stage IV. Based on a hypothetical cohort, the researchers estimated that if all cancers diagnosed at stage IV were discovered at stage III over a 5-year time period, there would be 51 fewer cancer-related deaths per 100,000 people. When detecting cancer at any stage prior to stage IV, there would be an estimated 15% reduction in all cancer-related deaths within 5 years. Although this was a retrospective analysis, there appears to be a clear opportunity for reduction in the burden of cancer with earlier detection; with more research, earlier detection may also lead to reductions in cancer-related deaths.¹⁰

Economic Impact of Cancer

In addition to the mortality risk associated with a diagnosis of cancer, there are significant economic implications. Economic burden is evaluated by assessing both direct (eg, hospitalization, office visits, emergency department visits, treatment) and indirect costs (eg, time lost) associated with a diagnosis of cancer.¹¹ The total direct cost of cancer care in the United States in 2015 was estimated to be $80.2 billion.3 Of that, over half (52%) of the costs were for outpatient or doctor office visits, while 38% were for inpatient hospital stays.³ Direct costs vary widely depending on the type of cancer that is diagnosed. For example, breast cancer in the United States was associated with a total annual cost of $16.5 billion, and prostate cancer had a total annual cost of $11.9 billion in 2010; these annual costs for breast cancer and prostate cancer are projected to increase 32% (≈$22 billion) and 42% (≈$17 billion), respectively by 2020.¹¹ Treatment costs, especially newer, more expensive targeted therapies, may increase direct costs associated with cancer.^6,11

In addition to a portion of the direct costs, patients and caregivers may be responsible for indirect costs, which may include the following:

Time required for receiving medical care

Morbidity (time lost from work or other activities)

Lost productivity (missed days of work and/or early mortality)

Indirect costs are not always associated with direct payment (eg, fee-for-service); costs are estimated based on various models that assign a monetary value to time spent or time lost due to cancer.^11,12 A study analyzing cancer deaths, median incomes, and life expectancy in 2015 demonstrated the enormous impact cancer has on the US economy.¹² An estimated $94.4 billion (95% CI, $91.7 billion - $97.3 billion) was lost in overall earnings (productivity) due to cancer, with an average lost earnings per cancer death of $191,900.12 Lung cancer accounted for the highest amount of lost earnings, totaling $21.3 billion. Colorectal cancer was second highest at $9.4 billion, with breast and pancreatic cancers following at approximately $6 billion each in lost earnings.¹² Considering the majority of the working-age population in the United States have employer-based health insurance, it is difficult to fully account for direct and indirect costs associated with cancer.¹¹ Patients and caregivers may lose health insurance coverage during the treatment of cancer due to limited opportunities for employment. Even with health insurance, high out-of-pocket costs may impact patient decisions to pursue further care and lead to delays in diagnosis and treatment.¹¹ Although these estimates provide some guidance, it is important to consider that the actual impact of cancer on individuals and society is likely even greater.

Current Cancer Screening Recommendations

In the United States, most cancers lack widely accepted or guideline-recommended screening methods. The National Cancer Comprehensive Network (NCCN) and the US Preventive Services Task Force (USPSTF) recommend routine screening for breast, cervical, colorectal, and lung cancers in specific subsets of the population.^7,13-17 Table 2^{5,7,13-15,17,18} depicts the most commonly used screening methods for each of these cancers, including the advantages and disadvantages of the associated test.^5,7,13-17 Available cancer screening tests have multiple advantages, but some limitations, such as ability to screen for only 1 cancer organ of origin at a time, limited specificity and/or sensitivity, and, for some tests, complexity and burden of testing.⁵ Sensitivity is defined as the test’s ability to correctly classify the patient as diseased, or the probability of a patient testing positive when disease is present.¹⁹ Specificity is defined as the test’s ability to correctly classify the patient as disease free, or the probability of a patient testing negative when there is no disease present.¹⁹ Screening tests that lack specificity can lead to false-positive results and unnecessary evaluations for confirmatory testing. A lack of sensitivity can lead to incomplete early detection of clinically significant cancers. Lack of ability to distinguish between clinically significant and clinically insignificant cancers can result in overdiagnosis and overtreatment. Breast, cervical, and colorectal cancers have established screening recommendations for the general population regardless of risk factors, whereas lung cancer screening is recommended in patients with specific risk factors, which include smoking.^7,13-17

Breast Cancer

Mammography is the primary method of breast cancer screening and is recommended by the NCCN guidelines annually for average-risk women starting at age 40 years, or by the USPSTF biennially for average-risk women starting at age 50 years.^7,13 Additionally, the ACS recommendations endorse annual screening starting at age 45 years. Individuals at higher risk have more specific recommendations regarding the age at which screening should begin and how frequently the mammograms should be offered. Screening with mammography has been shown to decrease mortality; however, there is decreased sensitivity in women with dense breasts as well as limited specificity resulting in frequent false-positive results requiring further confirmatory testing.¹³

Cervical Cancer

Cervical cytology, or Papanicolaou (PAP) test, is recommended every 3 years in average-risk women aged 21 to 29 years by the USPSTF.⁷ From age 30 to 65 years, average-risk women should either have a PAP test every 3 years or have a PAP test plus high-risk human papillomavirus (hrHPV) every 5 years. Although hrHPV or a PAP test may be used alone from ages 30 to 65 years, co-testing is preferred. Routine screening is not recommended after a hysterectomy or after the age of 65 years if the woman has had 10 years of regular screening with normal results.⁷ The 2012 ACS guidelines were endorsed by the NCCN; however, the ACS recently published guideline updates in 2020 recommending screening begin at age 25 years rather than age 21.¹⁷ Unlike the 2012 ACS guidelines where the PAP test was preferred, the 2020 ACS guidelines recommend primary HPV testing every 5 years through age 65.^16,17 If primary HPV testing is unavailable, then co-testing with HPV and cytology every 5 years or a PAP test every 3 years is acceptable. Additionally, HPV vaccination may decrease the efficiency of screening, specifically cytology-based screenings, yet there are currently no modifications of screening recommended if a patient has been vaccinated in the past.^16,17

Colorectal Cancer

Many options for screening colorectal cancer exist, including colonoscopy, flexible sigmoidoscopy, computed tomography (CT) colonography, and stool-based testing.¹⁴ Stool-based testing includes high-sensitivity guaiac- or immunochemical-based testing as well as multitarget stool DNA and occult blood testing (mt-sDNA).¹⁴ Screening should start at 50 years of age for average-risk men and women, according to the NCCN and at age 45 years according to the ACS. In the fall of 2020, the USPSTF circulated a draft guideline that calls for screening to start at age 45 years rather than the previously recommended age 50 years.^7,14,18 The frequency of screening varies greatly depending on the type of test and patient-specific risk factors. There are many considerations when comparing the various colorectal cancer screening methods (see Table 2^{5,7,13-15,17,18}). Colonoscopies are arguably the most invasive cancer screening method, yet they are the most common method of screening in the United States, in part because they allow for immediate removal of suspicious lesions. Conversely, stool-based testing is noninvasive and can conveniently be done at home; however, fecal occult blood tests have high false-positive rates and may lead to unnecessary follow-up procedures.¹⁵

Lung Cancer

Screening for lung cancer is done in patients who have a history of smoking with or without other risk factors for lung cancer, but is not recommended for an asymptomatic person of average risk.¹⁵ Low-dose CT (LDCT) scans utilized for qualifying patients based on risk factors are typically recommended annually, but may be done more frequently depending on the results of the first scan.^7,15 The USPSTF recommends screening in patients with a history of smoking of 30 pack-years; however, the NCCN screening guidelines include several additional risk factors, including, but not limited to second-hand smoke exposure, radon or occupational exposure, and cancer history.^7,15 LDCT scans are currently the only screening modality recommended and have an advantage of a reduced exposure to radiation compared with standard diagnostic CT. They are more efficacious in detecting adenocarcinoma and squamous cell carcinoma compared with chest x-rays.¹⁵

Prostate Cancer

The diagnosis of prostate cancer does not always require treatment; thus, early detection of prostate cancer may lead to overdiagnosis, unnecessary treatment, patient anxiety, and avoidable costs.²⁰ NCCN guidelines have a grade C recommendation for early detection of prostate cancer: with early detection offered only when patients fully understand benefits and the risks of participating, which is similar to the USPSTF recommendations.²⁰ Prostate-specific antigen (PSA) is one method of detection and is measured in a blood test, while a digital rectal exam (DRE) is a physical exam that may be used in conjunction with the PSA level.²⁰ Unfortunately, PSA is not a cancer-specific marker and instead is a prostate-specific marker. It may be elevated for a variety of reasons not linked to prostate cancer, such as infection, trauma, or ejaculation. Utilizing PSA testing has led to an increase in detection of early-stage disease and a decrease in detecting metastatic disease at diagnosis.²⁰ DRE tests are only considered in conjunction with PSA levels due to poor positive predictive value and to avoid unnecessary biopsies.²⁰ Neither ideal age nor frequency of screening for prostate cancer is established, nor are there clear universally agreed-upon recommendations for screening based on risk factors for prostate cancer.

Emerging Multicancer Detection Technology

Current screening methods assess for one cancer at a time, and many cancers currently do not have a viable option for early detection in the general population. The multicancer screening concept relies on a blood analysis designed to detect hallmarks of multiple cancers and may have the potential to be applied to cancer screening and early detection.^21,22 Compared with a tissue biopsy, blood-based tests, also referred to as liquid biopsies, can examine multiple analytes in the blood, including DNA mutations, DNA methylation (gene silencing markers), and proteins. Circulating cell-free DNA (cfDNA) is used in many blood-based assays because it is DNA released by a cell during apoptosis. The cfDNA can be analyzed for mutations and other alterations specific to cancer and methylation patterns specific to the tissue of origin.²¹ Blood-based liquid biopsies can detect multiple cancers with one test, and are minimally invasive—two advantages over standard tissue biopsies.

Tests that address multiple cancers simultaneously have the potential to extend early detection to a broader spectrum of malignancies. The ideal cancer screening test would detect cancer before symptoms develop. The test would have a high sensitivity (low false-negative rate) and high specificity (low false-positive rate), the ability to detect clinically significant cancers and avoid the detection of insignificant cancers, the ability to pinpoint the specific cancer type, be noninvasive and introduce low harm, be easily accessible and cost-effective^.5

CancerSEEK Test

CancerSEEK is a blood test that detects cfDNA and also identifies several protein biomarkers that are released by tumors.²¹ The test aims to detect multiple types of cancer by combining the detection of cfDNA and protein biomarkers. The assay identifies 8 protein biomarkers, which were chosen by researchers based on their ability to distinguish between patients with and without cancer, as shown in previous literature. The assay also identifies cancer via mutations in 1933 genomic positions, and each genomic position has multiple mutation possibilities, such as substitutions, insertions, or deletions. Preliminary performance of the test was evaluated in a trial of approximately 1000 patients with a cancer diagnosis who were compared with approximately 800 patients without cancer (Table 3).^23,24 The specificity of the test was over 99% in 8 cancer types: ovarian, liver, stomach, pancreatic, esophageal, colorectal, breast, and lung.²¹ Although the false-positive rate was low in the trial, it would be expected to be higher in the real-world setting when the test is applied to a healthy population without known cancer.²¹ The performance of such tests with respect to false-positive and false-negative rates is dependent on the test’s inherent characteristics as well as the prevalence of cancer in the population evaluated with the test. Findings show that sensitivity ranged from approximately 98% in ovarian and liver cancer and 33% in breast cancer, with a sensitivity of about 70% for the remaining cancers.²¹ The tissue of origin was correctly identified in approximately 80% of patients.²¹

The Detecting cancers Earlier Through elective mutation-based blood Collection and Testing (DETECT-A) trial is a prospective, interventional trial that enrolled 10,006 women aged 65 to 75 years with no history of cancer.²³ Positron emission tomography-computed tomography (PET-CT) was used to evaluate a positive test result. Of the 9911 participants evaluated, cancer was detected in 26 participants by the blood test, including cancers without current screening recommendations.²³ Of the 26 women with cancer, 17 had early-stage cancer and 14 were in organs in which there are currently no screening methods available, such as ovaries, kidney, and the lymphatic system.²³ The specificity during this trial was estimated to be 98.9%, which increased to 99.6% when done in combination with the PET-CT.²³ There were 24 false negatives, and the cancers that were missed by this blood test were breast, lung, and colorectal, of which 22 were early-stage cancers and have other screening methods.²³ This blood test is also being studied in the Detecting Cancers Earlier Through Elective Plasma-based CancerSEEK Testing - Ascertaining Serial Cancer Patients to Enable New Diagnostic (ASCEND) trial to compare patients with and without cancer. Accrual was completed in June 2020; results are awaited.²⁴

Galleri Test

The Galleri multicancer early detection (MCED) test identifies cfDNA circulating in the blood through next-generation sequencing, which recognizes DNA methylation.²⁵ The test aims to identify distinct methylation patterns that are associated with specific cancers to detect a number of those cancers early and simultaneously provide information about the organ of origin.²⁵ Four trials are evaluating this technology, including the Circulating Cell-free Genome Atlas (CCGA), STRIVE, SUMMIT, and PATHFINDER studies (Table 4).^26-29 The CCGA study served in the initial development of the test by analyzing blood and tumor tissue samples from 15,254 individuals from 142 sites in North America, including patients with newly diagnosed cancer (56%, N = 8584) and blood samples from patients without a diagnosis of cancer (44%, N = 6670). More than 50 different cancer types were included in the samples analyzed. The trial includes 3 subsets to evaluate the different analytic methods of MCED, the test’s ability to correctly identify the tissue of origin, and a confirmatory validation. Subsets 1 and 2 of the study have been completed with the third, a validation study, ongoing.²⁶ The preliminary trial results for the CCGA were presented at the 2019 American Society of Clinical Oncology (ASCO) meeting.²⁵ The trial included a sub-study of 6689 participants, of which 2482 had previously untreated cancer, and included 4207 without cancer.²⁵ The preliminary results showed that the MCED test could detect 12 types of cancer at early stages, including anorectal, colorectal, esophageal, gastric, head and neck, hormone receptor-positive breast, liver, lung, ovarian, and pancreatic cancers, in addition to multiple myeloma and lymphoid neoplasms. These 12 cancers are expected to account for over half of cancer deaths in the United States.⁶ The specificity was set at 99.3%, and tissue of origin was correctly identified with 93% accuracy. The test had a 67.3% (95% CI, 60.7%-73.3%) detection rate for the 12 prespecified cancer types across stages I to III, including 39% for stage I, 69% for stage II, and 83% for stage III. The overall detection rate for all cancer types was 43.9% (95% CI, 39.4%-48.5%) across stages I to III.²⁵

The STRIVE trial is ongoing and seeks to investigate and validate the ability of the MCED test to detect breast cancer (and other cancers) that might occur within 1 year by collecting blood samples from patients within 28 days of a screening mammogram.²⁷ The study aims to enroll about 100,000 women aged 18 years and older in the United States. The estimated primary completion date is June 2022. Another trial currently underway is the SUMMIT study, which is similar in design to the STRIVE trial, but investigating lung cancer detection in the United Kingdom.²⁸ The study aims to enroll 50,000 men and women aged 50 to 77 years who will be split into 2 groups based on the risk of lung cancer related to smoking history. Blood will be collected and an LDCT will be performed to validate the early lung cancer detection.²⁸ The primary completion date is estimated for August 2023. Finally, the PATHFINDER trial is the first to prospectively examine the application of the MCED test in a real-world, early detection setting where test results are returned to participants and their physicians.²⁹ It is recruiting approximately 6200 participants 50 years or older with varying levels of cancer risk and without a focus on any single cancer. The 2 cohorts in the study include elevated risk (defined as 1 of the following: smoking history of ≥100 cigarettes, a genetic cancer disposition, or a history of invasive or hematologic malignancy with definitive treatment completed >3 years prior to enrollment) and non-elevated risk. The results of the test will be returned to healthcare providers as “signal not detected” or “signal detected” and trigger a diagnostic evaluation based on specific institutional practice rather than study protocol. The study seeks to determine the performance of the MCED test in a setting that resembles routine testing of healthy individuals. It also aims to define what evaluations are needed to arrive at a diagnostic resolution after a “signal detected” result (cancer that is either diagnosed or ruled out). The study will evaluate health resource utilization, the number and types of tests and time required to reach diagnostic resolution as well as test performance (specificity, positive predictive value, and tissue of origin accuracy). Several patient-specific factors will be assessed, including quality of life, anxiety, perception, and satisfaction with the test.^29,30 The PATHFINDER trial will evaluate experience in the context of a broad healthy population, including clinical evaluations and the patient experience. If successful, the experience of PATHFINDER will be helpful in defining the potential application of MCED for the general population and early detection of a variety of cancers. The trial has an estimated primary completion date of May 2021.²⁹

PanSeer Test

The PanSeer test detects DNA methylation patterns linked to gene silencing that may contribute to cancer development. Of note, the test is designed to identify cancer in asymptomatic individuals and is unlikely to predict who will develop cancer if not present at the time of screening.³¹ The longitudinal study evaluating this test used plasma samples from the Taizhou Longitudinal Study (TZL). In the TZL, 123,115 healthy subjects in China aged 25 to 90 years provided plasma samples. The subjects were monitored over 10 years for cancer, among other chronic conditions and specific diseases, at 3-year intervals via detailed questionnaires and additional plasma and tissue samples.³² The preliminary results of the test included an evaluation of approximately 400 blood samples from cancer-free participants and 400 blood samples from participants who were diagnosed with cancer within 4 years of enrollment.³¹ The cancers included were stomach, colorectal, liver, lung, and esophageal. The test showed a specificity of 96% in patients after being diagnosed with 1 of 5 types of cancer, and the test detected cancer in 95% of asymptomatic participants who were then diagnosed later.³¹ One of the limitations of the test is it does not detect the tissue of origin; it detects abnormalities that need further workup to determine the exact location of the cancer. However, if validated, this test could be used as a first step in screening, meaning a positive result will prompt further diagnostic testing to localize the suspected cancer.³¹

Emerging Single-Cancer Detection Technologies

Several single-cancer detection methods are under investigation. One of the tests that has entered validation is a multiomics test for colorectal cancer.³³ The single-cancer detection (SCED) blood test is a multiomic blood test of cfDNA and protein biomarkers to detect early cancer.³³ The results from the AI-EMERGE trial were presented at the ASCO Gastrointestinal Cancers Symposium in January 2020.³³ By comparing blood and stool samples between healthy patients undergoing routine colonoscopies and patients diagnosed with colorectal cancer, the researchers concluded the test has a 94% sensitivity and specificity rate for stage I and II colorectal cancer and a sensitivity of 91% and specificity of 94% in stage III and IV colorectal cancer.³³

Providing a stool sample was optional, and only about half of participants chose to do so, which underscores the known hesitation of patients to undergo colorectal cancer screening in this manner.33 The specificity for the SCED blood test was similar to the fecal immunochemical (FIT) test, yet the sensitivity was much higher at 100% versus 67% for the FIT.33

A second trial, PREEMPT CRC, is expected to further validate the specificity and sensitivity of the assay by comparing the results from the SCED blood test to routine colonoscopy results in average-risk participants.³⁴ The prospective, observational trial will enroll around 14,000 participants and has an expected completion date of July 2021.³⁴

Conclusions

With cancer cases on the rise, effective screening methods and novel modalities are needed. Cancer screening in the general population is recommended for a small number of cancers, including breast, cervical, and colorectal cancers. Multicancer detection blood tests in development are designed to address many of the limitations associated with current screening methods. Further validation through prospective clinical trials is underway, and if validated, blood-based assays may allow for minimally invasive early detection of multiple cancers, including neoplasms that currently are not detected early because of a lack of effective screening tests. It remains to be determined how MCED tests might be used in practice. One can envision periodic blood-based testing, for example, annually or every several years. Tests with robust organ of origin information may permit a specific diagnostic evaluation to confirm or rule out the suggested cancer in individual patients.

Author affiliation: Tomasz M. Beer, MD, is deputy director and professor of medicine, Oregon Health & Science University Knight Cancer Institute, Portland, OR. He serves as Chief Medical Officer of the OHSU Knight Cancer Institute’s Cancer Early Detection Advance Research Center (CEDAR).

Funding source: This activity is supported by an educational grant from GRAIL, Inc.

Author disclosure: Dr Beer has the following relevant financial relationships with commercial interests to disclose:

Grant/Research Support: Alliance Foundation Trials, Astellas Pharma, Boehringer Ingelheim, Corcept Therapeutics, Endocyte Inc, Freenome, GRAIL Inc, Harpoon Therapeutics, Janssen Research & Development, Medivation, Sotio, Theraclone Sciences/OncoResponse, Zenith Epigenetics

Consultant: Arvinas, Astellas Pharma, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Bristol Myers Squibb, Constellation, GRAIL Inc, Novartis, Pfizer, Sanofi

Stock/Shareholder: Arvinas, Salarius Pharmaceuticals

Authorship information: Substantial contributions to the concept and design; analysis and interpretation of data; and critical revision of the manuscript for important intellectual content.

Address correspondence to: beert@ohsu.edu

Medical writing and editorial support: Sara Fisher, PharmD, and Brittany Hoffmann-Eubanks, PharmD, MBA

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