This contractor will provide limited coverage for molecular tests to aid in
the diagnosis or exclusion of lung cancer in a patient with an indeterminate
pulmonary nodule (IPN) following a non-diagnostic bronchoscopy when ALL of the
following conditions are met:

  1. The beneficiary has undergone bronchoscopy for an indeterminate pulmonary nodule AND 
    1. The bronchoscopy has failed to provide a specific histopathological diagnosis such that further diagnostic procedures are considered necessary to pursue a specific diagnosis (non-diagnostic bronchoscopy); AND 
    2. Test results will be used to meaningfully inform patient management within the framework of nationally recognized consensus guidelines.
    3. If medically reasonable and necessary following established guidelines, the nodule cannot be evaluated by an alternate methodology (EBUS, FNA, etc.) for a specific diagnosis.
  2. The beneficiary does NOT have any of the following:
    1. Personal history of cancer 
    2. Current diagnosis of cancer or high clinical suspicion for cancer
    3. An overall low risk for pulmonary malignancy such that test results would not meaningfully alter patient management and significantly improve patient outcomes.
    4. An overall high risk for pulmonary malignancy such that test results would not meaningfully alter patient management and significantly improve patient outcomes.
  3. The beneficiary has not been tested with the same or similar assay for the same clinical indication.
  4. The beneficiary is within the population and has the indication for which the test was developed and is covered. The lab providing the test is responsible for clearly indicating to treating clinicians the population and indication for test use.
  5. The test has demonstrated clinical validity and utility, establishing a clear and significant biological/molecular basis for stratifying patients and subsequently selecting (either positively or negatively) a clinical management decision in a clearly defined population. 
  6. Clinical validity of any analytes (or expression profiles) measured must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population.
  7. Rule-out tests should have a high sensitivity and negative predictive value (NPV) such that patients can be safely selected for a less aggressive management strategy without delay to diagnosis due to false negative results.
  8. Rule-in tests should have a high specificity and positive predictive value (PPV) such that patients can be safely selected for more aggressive management without significantly increasing procedures in patients without cancer due to false positive results.
  9. The test demonstrates analytical validity including both analytical and clinical validations. If the test relies on an algorithm (which may range in complexity from a threshold determination of a single numeric value to a complex mathematical or computational function), the algorithm must be validated in a cohort that is not a development cohort for the algorithm.
  10. Tests utilizing a similar methodology or evaluating a similar molecular analyte to a test for which there is a generally accepted testing standard or for which existing coverage exists must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the same intended-use population. New tests that become available with significantly improved performance may render older tests no longer compliant with this policy.
  11. The test successfully completes a Molecular Diagnostic Services Program (MolDX) technical assessment that ensures the test is reasonable and necessary as described above.

NOTE: Next Generation Sequencing (NGS) performed to identify genetic variants
in samples classified as malignant is not within the scope of this policy but
may fall under other established policies.

**Lung Cancer Screening**

****

Lung cancer is the leading cause of cancer-related deaths in the United
States.1 It is estimated that 236,740 new cases of lung and bronchial cancer
will have been diagnosed in the United States in 2022 (117,910 in men and
118,830 in women) with 130,180 anticipated deaths (68,820 in men and 61,360 in
women).1 Earlier diagnosis has significant impact on clinical outcome, as
5-year survival increases from 6%-9.5% for distant-stage disease, to 33-44%
for regional disease, and 60-75% for localized disease,1 although there have
been recent improvements in non-small cell lung cancer outcomes across stages
with the advent of targeted and molecular therapies.2 Data from larger
randomized control trials such as the National Lung Screening Trial (NLST) and
the Dutch-Belgian Randomized Lung Cancer Screening Trial (Nederlands-Leuvens
Longkanker Screenings Onderzoek [NELSON]) supports low-dose CT (LDCT)
screening in high-risk individuals based on smoking criteria and age.3-5 A
noticeable decline in advanced-stage lung cancer diagnosis with a
corresponding increase in incidence of localized stage disease was observed
between 2013 and 2018 following recommendation for lung cancer screening by
the United States Preventive Services Task Force (USPSTF).6 Due to increased
strength of evidence supporting annual screening with LDCT for high-risk
individuals, USPSTF issued updated screening guidelines in March of 2021,
expanding eligibility to adults aged 50 to 80 years who have a 20 pack-year
smoking history and currently smoke or have quit within the past 15 years.6
The Centers for Medicare & Medicaid Services (CMS) covers annual LDCT
screening for appropriate Medicare beneficiaries with significant smoking
history up to 77 years of age if they participate in shared decision-making
before their first screening LDCT.7 LDCT screening is also recommended by the
2021 CHEST Guideline and Expert Panel Report on Screening for Lung Cancer.8

Although there is consensus on the value of LDCT screening, uncertainty
remains about the appropriate duration of screening and age of screening
cessation, with NCCN recommending annual screening until the patient is no
longer a candidate for definitive treatment.9 There are also potential risks
associated with LDCT screening including false negative as well as false
positive results that can lead to unnecessary tests and invasive procedures,
complications from the diagnostic workup, overdiagnosis of incidental
findings, short-term anxiety due to indeterminate results, and radiation
exposure.9 As a result of increased implementation of screening guidelines,
the incidence of nodules detected on CT continues to rise, and an estimated
1.5 million nodules are detected each year in the United States.10 Most lung
nodules found on LDCT are benign,3,4 such that lung cancer prevalence in the
screening setting is 0.8-2.2% and approximately 0.11% in nodules incidentally
detected when imaging is performed for other reasons.10 An LDCT screen is
defined as "positive" if the size and morphologic features of the detected
nodule results in a recommendation for follow-up testing in addition to
recommended annual screening based on published guidelines.8 Approximately 7%
of patients with false positive results go on to an invasive procedure, most
often bronchoscopy.9,11,12

**Indeterminate Pulmonary Nodules (IPN) Risk Assessment and Management
Guidelines**

The American College of Chest Physicians (ACCP) Evidence-Based Clinical
Practice Guidelines define an indeterminate nodule as any nodule that is not
calcified in a benign pattern and is lacking clearly benign features such as
intramodular fat indicative of hamartoma or a feeding artery and vein typical
for arteriovenous malformation.13 Factors such as nodule morphology, size,
attenuation, and clinical context harbor varying risks of malignancy and the
probability of malignancy (low, intermediate, high) determines further
management, which is often either continued CT-surveillance PET/CT, and tissue
sampling including percutaneous needle biopsy, bronchoscopic biopsy, or
surgical biopsy.14,9 Nodule attenuation (solid, part-solid, ground glass
opacity), size (diameter or volume), and rate of growth factor strongly into
multiple management guidelines.13,15,16,17,9 NCCN guidelines delineate cut-off
values for size, follow-up interval, and intervention depending on nodule
appearance as solid, part-solid, or non-solid on initial LDCT screen and
subsequently consider level of clinical suspicion of lung cancer.9 The
Fleischner Society Guidelines for nodules discovered outside of LDCT cancer
screening also propose follow-up methods depending on whether a nodule is
solid or sub-solid. Additional factors considered for management include the
number of nodules, and size or volume of each nodule along with clinical risk
factors.15 The ACCP outlines a similar methodology for indeterminate nodules
discovered in the screening setting as well as those detected incidentally
wherein the follow-up strategy is dependent on nodule appearance, size, and
risk or probability of malignancy.13

Clinical risk factors associated with a higher risk of malignancy include
cigarette smoking, age, occupational and environmental exposures, pulmonary
fibrosis, chronic obstructive pulmonary disorder (COPD), personal history of
lung cancer, and female sex.14 ACCP Practice Guidelines recommend that
clinicians estimate the pretest probability of malignancy either qualitatively
by using their clinical judgement and/or quantitatively by using a validated
model. Pretest probability of malignancy enables selection and subsequent
interpretation of diagnostic tests as depicted in Table 1 below.13 Several
quantitative risk models exist to facilitate decision-making by incorporating
clinical and radiologic factors into a single risk score that summarizes
likelihood of malignancy.18-20 These models can be utilized alongside clinical
judgement and recommended guidelines to guide the next management step.14 The
Herder model incorporates PET avidity into the Mayo Clinic Model to improve
diagnostic value,21 whereas the TREAT model was designed for use in the
surgical clinic and incorporates hemoptysis and PET avidity, assuming a higher
prevalence of malignancy.22 Risk calculator performance varies depending on
the lung cancer prevalence and clinical characteristics of the original study
population.23 Therefore, risk estimates should be interpreted with caution,
taking the patient's clinical context and factors such as geographical
location into consideration. Recent studies suggest that physicians generally
have good intuition regarding risk assessment of IPNs  and while many do not
document a quantitative prediction of malignancy in advance of tissue
diagnosis, qualitative risk statements generally correlate with quantitative
risk.25 NCCN Guidelines for Lung Cancer Screening encourage a
multidisciplinary approach to evaluation for the suspicion of lung cancer
including input from thoracic radiology, pulmonary medicine, and thoracic
surgery, and may include the use of a lung nodule risk calculator to inform
probability assessment. NCCN cautions that risk calculator use is not a
substitute for multidisciplinary pulmonary management as geographic and other
factors can influence calculator accuracy.9

**Table 1. ACCP: Assessment of the Probability of Malignancy.** **13**

**Assessment Criteria**

|

**Probability of Malignancy**  
  
---|---  
  
Low (<5%)

|

Intermediate (5%-65%)

|

High (>65%)  
  
**Clinical factors alone (determined by clinical judgement and/or use of a
validated model)**

|

Young, less smoking, no prior cancer, smaller nodule size, regular margins,
and/or non-upper-lobe location

|

Mixture of low and high probability features

|

Older, heavy smoking, prior cancer, larger size, irregular/spiculated margins,
and/or upper-lobe location  
  
**FDG-PET scan results**

|

Low-moderate clinical probability and low FDG-PET activity

|

Weak or moderate FDG-PET scan activity

|

Intensely hypermetabolic nodule  
  
**Nonsurgical biopsy results (bronchoscopy or TTNA)**

|

Specific benign diagnosis

|

Nondiagnostic

|

Suspicious for malignancy  
  
**CT scan surveillance**

|

Resolution or near-complete resolution, progressive or persistent decrease in
size, or no growth over  years (solid nodule) or  3-5 years (subsolid
nodule)

|

NA

|

Clear evidence of growth  
  
FDG = fluorodeoxyglucose; NA = not applicable; TTNA = transthoracic needle
aspiration

Guidelines largely agree on management of low and high risk IPNs.9,13-17
Nodules with low probability of malignancy should be monitored with CT
surveillance, whereas those with high probability of malignancy merit more
aggressive evaluation and consideration for surgical resection.26 However,
there is heterogeneity in management recommendations of IPNs with intermediate
malignancy risk.14 Additional evaluation options for intermediate nodules
include short-term interval CT, fluorodeoxyglucose (FDG) PET, non-surgical or
surgical biopsy depending on the patient's risk of malignancy, health status,
preference, and clinical setting.14 Studies have also shown that many
physicians do not follow management guidelines, introducing further
heterogeneity in management and potential for suboptimal care with inadequate
work-up, prolonged surveillance or potentially harmful unnecessary
procedures.24,27 For example, a study of pulmonary nodule evaluation in the
usual care setting outside of a lung cancer screening study or dedicated
pulmonary nodule clinic found 18% of patients receiving over-evaluation
consisting of prolonged surveillance and biopsy and 27% receiving less intense
evaluation than recommended by guidelines, with radiologist recommendation as
the strongest predictor of intensity of evaluation.27 However, standardized
reporting of radiologic findings has helped to increase guideline
compliance.27,28 Additional improvement to risk stratification beyond the
available clinical and radiologic features is needed to decrease unnecessary
biopsy referrals and costs, especially in the intermediate risk group that is
most likely to undergo further testing for benign disease.

**Bronchoscopy**

****

Bronchoscopy is a common approach to tissue sampling and is frequently used in
patients with IPNs and an intermediate-risk of malignancy, for whom guidelines
show heterogeneity in management recommendations ranging from CT-surveillance
to non-surgical biopsy. Bronchoscopy is a relatively safe procedure with less
than 1% of cases complicated by pneumothorax.29 Approximately 500,000
bronchoscopies are performed annually in the United States of which
approximately half are done for lung cancer evaluation.30 Nevertheless,
bronchoscopy has lower sensitivity for smaller and peripherally-located
nodules and up to 40% of bronchoscopies lead to a non-diagnostic outcome
wherein the clinician cannot obtain a clinically actionable benign or
malignant diagnosis. Physicians are subsequently faced with the dilemma of
whether to monitor such patients with CT surveillance or proceed to a surgical
lung biopsy or transthoracic needle biopsy associated with a greater risk of
morbidity, such as pneumothorax or hemorrhage, or mortality.31

**Biomarkers to Improve Diagnostic Yield of Bronchoscopy**

****

Biomarkers can serve as an adjunct to bronchoscopy by resolving equivocal
cytology32 or improving risk-stratification to inform further patient
management. Recently published examples include detection of cancer-associated
deoxyribonucleic acid (DNA) methylation and gene mutations in bronchial
washings performed during fiberoptic bronchoscopy for diagnosis of lung
cancer,33 development of an exploratory bronchoalveolar lavage (BAL) genomic
classifier aimed at detecting tumor-derived mutations by targeted sequencing
of BAL cell free DNA (cfDNA),34 and validation of a **** multiple logistic
regression model including methylated tumor DNA from the _homeobox A9 (_ HOXA)
gene in bronchial lavage along with clinical factors such as age and smoking
status as a supplementary diagnostic tool for lung cancer detection,35 among
others. While many approaches are in the research and development pipeline,
few have been commercialized and incorporated into clinical practice36 as
further studies are required to determine clinical validity and utility. This
evidence summary will focus on in-depth review of commercialized molecular
assays that aim to improve risk stratification of indeterminate pulmonary
nodules following non-diagnostic bronchoscopy, acknowledging that additional
molecular assays exist in various stages of development.

**First Generation Gene Expression Profiling (GEP) Test: Percepta Bronchial
Genomic Classifier (BGC)**

The Percepta BGC is a messenger-ribonucleic acid (RNA) assay performed on
cytology brushings of bronchial epithelial cells collected during bronchoscopy
from current or former smokers undergoing evaluation for suspected lung cancer
and is performed in the event of non-diagnostic bronchoscopy. The test uses
patient age along with microarray technology to measure the expression of 23
lung cancer associated genes to improve the diagnostic yield of bronchoscopy.
The assay was designed as a high sensitivity "rule-out" test for patients with
a non-diagnostic bronchoscopy and intermediate-risk of malignancy, in order to
re-classify intermediate pre-test cancer risk to low post-test risk with a
nondiagnostic bronchoscopy and negative classifier result.31

BGC classifier development was rooted in preceding studies that demonstrated a
molecular field of injury consisting of gene expression changes in airway
epithelial cells as a function of cigarette smoking.37,38 The classifier was
developed in current or former smokers undergoing bronchoscopy for suspected
lung cancer across 28 centers in the United States, Canada, and Ireland in two
independent, prospective, multicenter observational studies, known as the
Airway Epithelial Gene Expression in the Diagnosis of Lung Cancer (AEGIS-1 and
AEGIS-2) Trials.31 Exclusion criteria consisted of age <21 years, smoking <100
cigarettes, concurrent cancer or history of lung cancer. The prevalence of
lung cancer in AEGIS-1 was 74% and 78% in AEGIS-2. The median age of patients
in AEGIS-1 was 62 years (interquartile range 55-70) and 64 years
(interquartile range 57-71) in AEGIS-2.31 Both trials included a diverse group
of patients, with nearly 20% being African American.31 A set of patients from
AEGIS-1 (223 patients diagnosed with lung cancer and 76 patients diagnosed
with benign disease) was randomly selected for classifier training39 whereas
298 patients from AEGIS-1 and 341 patients from AEGIS-2 were utilized in
classifier validation.31

In the validation set, 43% of bronchoscopies were non-diagnostic for lung
cancer (95% Confidence interval (95% CI), 39-46), including for 25% of
patients in whom lung cancer was ultimately diagnosed (95% CI, 21-29). A
"diagnostic" bronchoscopy was defined to yield a confirmed lung cancer
diagnosis. Patients' pre-bronchoscopy risk of malignancy was assessed by each
treating physician based on their subjective assessment and the results were
divided into categories of low (<10%), intermediate (10-60%), and high (>60%)
probability of malignancy with a corresponding malignancy prevalence of 5%,
41%, and 95%, respectively. Physicians and patients were not informed of
classifier results. Bronchoscopy sensitivity for lung cancer detection was 74%
(95% CI, 68 to 79) in AEGIS-1 and 76% (95% CI, 71 to 81) in AEGIS-2. In
AEGIS-1, the area under the receiver-operating-characteristic curve (AUC) for
the classifier was 0.78 (95% CI, 0.73 to 0.83) with a sensitivity of 88% (95%
CI, 83 to 92) and a specificity of 47% (95% CI, 37 to 58). The AUC of the
classifier in AEGIS-2 was 0.74 (95% CI, 0.68 to 0.80), with a sensitivity of
89% (95% CI, 84 to 92), and a specificity of 47% (95% CI, 36 to 59). There was
no statistically significant difference in classifier performance in AEGIS-1
vs AEGIS-2. Combining bronchoscopy with the classifier led to an increased
sensitivity of 96% (95% CI, 93 to 98) in AEGIS-1 and 98% (95% CI, 96 to 99) in
AEGIS-2, independent of lesion size and location. The negative predictive
value (NPV) of the classifier in 101 patients with an intermediate pretest
probability of cancer and nondiagnostic bronchoscopy was 91% (95% CI, 75 to
98),31 whereas in 426 patients with a high pretest probability of cancer, the
NPV was 38% (95% CI, 15-65).31

Overall, 487 patients were diagnosed with lung cancer and 120 had non-
diagnostic bronchoscopy, of which 13 were classifier negative (false
negatives). Three of these were in the intermediate risk category and 10 had a
high pretest risk of malignancy. Patients with false negative results should
not experience significant delay to diagnosis as patients with a nondiagnostic
bronchoscopy and negative classifier score should undergo CT surveillance as
standard of care when an immediate invasive strategy is not utilized.31 The
positive predictive value (PPV) in the intermediate risk population was 40%
(95% CI 27-55) and 84% (95% CI 75-91) in the high pretest probability group.
Given the modest PPV in the intermediate risk group (40%), the authors
concluded that a positive classifier result does not warrant decision
alteration between invasive strategy and imaging-surveillance.31 A negative
classifier result has potential clinical utility in patients with a
nondiagnostic bronchoscopy and an intermediate probability of cancer, as a
negative classifier score may warrant a more conservative diagnostic strategy
involving imaging surveillance instead of invasive procedures as the next step
in patient management.31 Analytical performance of the bronchial genomic
classifier was reported in Hu et al40.

Clinical utility was evaluated by examining potential procedure reduction in
the AEGIS trials as a result of classifier use41 and through a survey of
pulmonary physicians presented with clinical cases.42 The Percepta Registry
Cohort was established as a multicenter prospective registry including
academic and community medical centers aimed at observing physician management
of patients with pulmonary nodules following nondiagnostic bronchoscopy in a
setting with and without classifier results.43 Lee et al43 found that 34.3% of
patients with low or intermediate risk of malignancy and a clinician-
designated plan for a subsequent invasive procedure had a reduction in
malignancy risk and 73.9% of these patients had a subsequent change in
management plan from invasive procedure to surveillance with the majority
avoiding a procedure up to 12 months following the initial evaluation. The
study did not find a statistically significant delay to diagnosis in the
classifier false negative patients nor a significant increase in advanced
cancer stage at diagnosis.43

****

**Second Generation GEP: Percepta Genomic Sequencing Classifier (GSC)**

The Percepta Genomic Sequencing Classifier (GSC) is a second-generation
classifier currently offered for clinical use in replacement of the BGC. It
was developed from whole transcriptome RNA sequencing along with clinical
factors, with multiple thresholds allowing for both up-classification and
down-classification of malignancy risk in patients with non-diagnostic
biopsy.8,44 The up-classification is intended to be an improvement on the
first generation Bronchial Genomic Classifier, which was designed to be solely
a "rule out" test for intermediate-risk patients. The GSC final model uses
1232 genes and four clinical covariates - including pack-years, age, and
interfering factors such as inhaled medication use and specimen collection
timing.44 The GSC was developed using samples from current and former smokers
who underwent bronchoscopy for suspected lung cancer as part of the AEGIS-1
and AEGIS-2 trials and the BGC Registry, wherein patients were split into
training and validation cohorts. Classifier performance characteristics from
the validation set (N=412) are listed in Table 2 below, demonstrating similar
performance as a rule-out test for intermediate and low risk categories
compared with the first generation BGC.

**Table 2. Lung cancer genomic sequencing classifier validation performance.**
**44**

**AUC**

|

**Pre-test Cancer Risk**

|

**Cancer prevalence**

|

**Cancer Risk re-stratification**

|

**Specificity (% and 95% CI)**

|

**Sensitivity (% and 95% CI)**

|

**Post-test NPV/PPV (% and 95 CI)**

|

**% Re-stratified**  
  
---|---|---|---|---|---|---|---  
  




73.4% [95% CI 68.3-78.4]

|

Low

|

5%

|

Low to Very Low

|

57.4% [44.8-69.3]

|

100% [39.8-100]

|

100% NPV [91.0-100]

|

54.5%  
  
Intermediate

|

28.2%

|

Intermediate to Low

|

37.3% [27.9-47.4]

|

90.6% [79.3-96.9]

|

91.0% NPV [80.8-96.0]

|

29.4%  
  
Intermediate to High

|

94.1% [87.6-97.8]

|

28.3% [16.8-42.3]

|

65.4% PPV [43.8-82.1]

|

12.2%  
  
High

|

73.6%

|

High to Very High

|

91.2% [76.3-98.1]

|

34.0% [25.0-43.8]

|

91.5% PPV [77.9-97.0]

|

27.3%  
  


29.4% of intermediate-risk patients had an "actionable negative" result, such
that if the test were to lead to surveillance imaging in 10 patients, 9 would
be expected to have benign lesions and safely avoid further testing, whereas
one patient with a malignant lesion could potentially experience a delay in
further evaluation.44 12.2% of the intermediate cohort was up-classified form
intermediate to high risk with a PPV of 65.4%. Thus, if the test were to
result in more aggressive management, approximately two patients with
malignancy would experience additional invasive testing or treatment, whereas
one patient with a benign lesion would do the same.44 The potential impact of
the classifier on the rate of invasive procedures was assessed in the AEGIS I
and II cohorts.45 This was done by estimating the potential reduction in the
number of procedures in patients who have been re-classified by the GSC,
assuming that the classifier would have been used in procedure decision-
making.45 As a result of classifier use, 50% of patients with benign lesions
as well as 29% of those with malignancy undergoing additional invasive
procedures prior to definitive surgery could have potentially avoided invasive
procedures.44,45 Analytical validation of the GSC was published by Johnson et
al46.

Raval et al47 conducted an observational study that retrospectively assessed
data from four clinical sites (two academic and two community medical centers)
that regularly use the GSC in clinical practice. 42% of patients had a change
in risk category following GSC results compared to pre-procedure risk of
malignancy. Potential clinical utility was modeled using performance
characteristics from prior studies and modeling was based on hypothetical
assumptions that risk up-classification from high to very high would lead to
referral for surgical resection as the next management step and down-
classification to low or very low risk of malignancy would result in CT
surveillance as the next step.47 The authors aim to update this study to
assess the true impact of Percepta GSC results in the context of outcomes data
including future diagnosis of cancer or benign disease when that information
becomes available.47 Finally, Sethi et al48 reported results from a decision
impact study demonstrating that up-classification of malignancy risk from high
to very high can potentially allow more patients to proceed more rapidly to
curative therapy, with a decrease in intervening diagnostic procedures.

Accurate malignancy risk stratification is essential to guide diagnostic
evaluation of IPNs in a manner that maximizes diagnosis of malignancy while
simultaneously minimizing unnecessary risk, associated anxiety, and cost of
benign IPN evaluation.14 Guidelines on the management of intermediate risk
patients with IPNs show heterogeneous recommendations. Moreover, management
options in these patients include bronchoscopy, an invasive procedure with an
overall diagnostic yield of 69% according to a recent study.52 Therefore,
whenever possible, IPNs in these patients should be investigated using
noninvasive procedures in order to avoid morbidity in patients without
cancer.9,49 Molecular biomarkers can fulfill this need.

The evidence published to date has demonstrated clinical utility and validity
of molecular biomarkers as high sensitivity "rule-out" tests for current or
former smokers with indeterminate pulmonary nodules and intermediate risk of
malignancy who have undergone a non-diagnostic bronchoscopy. These tests can
effectively re-classify risk of malignancy from pre-test "intermediate" to
post-test "low" risk in patients with a non-diagnostic bronchoscopy and
negative classifier result. This re-classification can inform the management
of post-test low-risk patients, enabling selection of CT-surveillance as the
immediate follow-up to a non-diagnostic biopsy versus additional invasive
tissue sampling. The clinical validity was effectively demonstrated by
Silvestri et al31, wherein use of the Percepta BGC increased the diagnostic
yield of bronchoscopy such that the combination of bronchoscopy with the BGC
classifier led to an increased sensitivity of 96% (95% CI, 93 to 98) in the
AEGIS-1 and 98% (95% CI, 96 to 99) in the AEGIS-2 trials, independent of
lesion size and location. In comparison, the sensitivity for lung cancer
detection of bronchoscopy alone was 74% (95% CI, 68 to 79) in AEGIS-1 and 76%
(95% CI, 71 to 81) in AEGIS-2. The NPV of the classifier in 101 patients with
an intermediate pretest probability of cancer and nondiagnostic bronchoscopy
was 91% (95% CI, 75 to 98).31 Similar classifier performance was demonstrated
by the second generation Percepta GSC test.44

In patients with an intermediate pretest probability of cancer, the AEGIS
studies reported only three false negative classifier results. Patients with
false negative "low risk" classifier results should not experience significant
delay to diagnosis as patients with a nondiagnostic bronchoscopy and negative
classifier score should still undergo CT surveillance as a standard of care
when an immediate additional invasive strategy is not utilized.43 This was
supported by lack of significant delay to diagnosis in classifier negative
patients and no significant increase in advanced cancer stage at diagnosis in
the prospective multicenter study conducted by Lee et al using the Percepta
Registry Cohort.43 This study demonstrated clinical utility through reduction
in procedure recommendations in patients with nondiagnostic biopsy and
negative classifier results.43 Nevertheless, there are several important
limitations. Namely, the study was not a randomized comparison of management
and outcomes in patients whose care was guided by use of the Percepta BGC to
those whose care was not guided by classifier results. There was also
variability in practice patterns amongst the medical sites included in the
Percepta Registry, in that some sites chose close surveillance as a result of
Percepta down-classification, whereas others retained their post-test plan for
invasive procedures in this patient group. Furthermore, a significant number
of patients lacked consensus in adjudicated final diagnosis following expert
panel review, most often as a result of insufficient clinical information at
follow-up, introducing a potential source of selection bias.43 Additional
confounding factors include the timing of specimen collection, in that 97% of
patients in the AEGIS cohorts had sample collection prior to other
cytology/pathology sampling whereas only 38% of BGC registry samples were
collected prior to other testing (p<0.001), introducing potential confounding
from gene expression signatures resulting from tissue injury, which was
addressed by the second generation Percepta GSC test.44 Finally, the study
authors note that the observed classifier impact could have been greater if
clinical sites had experience using the test prior to study enrollment.

The studies described herein have demonstrated that molecular tests with high
sensitivity and NPV can be used to rule out malignancy in current or former
smokers with intermediate risk lung nodules and a nondiagnostic bronchoscopy
to meaningfully reduce the number of procedures in patients without lung
cancer. However, their ability to rule-in malignancy is not as clear. The
moderate PPV of 65% in the intermediate risk category observed in the GSC
could lead to increased procedures in one out of three patients without
malignancy, while potentially expediting malignancy diagnosis in two, when
compared to the standard of care. The clinical utility of this risk/benefit
trade-off remains to be demonstrated. The benefit of testing patients with a
low pre-test risk of malignancy for whom CT surveillance is the recommended
follow-up strategy according to practice guidelines is also unclear, as re-
stratification to a very low risk category leads to the same recommended
intervention (i.e. CT surveillance).

Current clinical guidelines show solid performance in the appropriate clinical
context, in that detected suspicious nodules are followed in a manner that
minimizes extensive stage-shift with concurrent effort at reduction in
invasive procedures in patients with benign lesions.50 Molecular biomarkers
must demonstrate clear value of re-stratification beyond currently available
clinical and radiologic strategies, such that the post-test risk of malignancy
results in impactful changes in patient management with improved outcomes.51
All tests should be clinically validated in their intended-use population and
will be deemed reasonable and necessary for clinical use only in that
population. Patients whose pretest risk of malignancy is too low or too high
to merit meaningful changes in management that result in improved outcomes are
not eligible for testing. The benefit of re-stratification should be clearly
defined and demonstrated, preferably through real-world randomized clinical
utility studies.

Rule-out tests that aim to decrease the pretest probability of malignancy
should have a high sensitivity and NPV. As false negative results are
unavoidable, it is imperative to demonstrate that they do not result in a
significant delay nor advanced stage at diagnosis compared to standard risk
stratification measures. Rule-in tests that aim to up-classify patients by
increasing pretest probability of malignancy should have a high specificity
and PPV. In patients whose risk is up-classified by a given molecular test, it
is important to demonstrate a significantly decreased time to diagnosis and
avoidance of intervening diagnostic procedures in the setting of malignancy,
along with a lack of significant increase in procedures for falsely up-
classified patients with benign nodules.

Decision-making in patients with IPNs is complex, and a given molecular
biomarker offers a single data point to be considered within the broader
clinical context. Additional factors such as surgical risk, patient
preference, resource availability and physician experience also play a role in
IPN management.

Finally, reference to specific tests in this document does not imply coverage
by this contractor. Abstracts and preprints of journal articles were not
considered, as they were not fully reviewed peer-reviewed publications at the
time of drafting this local coverage determination. This coverage decision
will be periodically re-evaluated based on evolving literature and national
consensus guidelines.