This policy concerns the use of molecular diagnostic laboratory tests (tests
of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and / or proteins) as
a predictive classifier for non-small cell lung cancer (NSCLC).

Molecular classifiers are considered reasonable and necessary when
beneficiaries meet all of the following criteria:

  1. The patient has a non-squamous NSCLC with a tumor size < 5cm, and there are no positive lymph nodes (i.e. American Joint Committee on Cancer (AJCC) Eighth Edition Stages I and IIa).
  2. The patient is sufficiently healthy to tolerate chemotherapy.
  3. Adjuvant platinum-containing chemotherapy is being considered for the patient.
  4. The test is ordered by a physician who is treating the patient for NSCLC (generally a medical oncologist, surgeon, or radiation oncologist) to help in the decision of whether or not to recommend adjuvant chemotherapy

Non-Small Cell Lung Cancer (NSCLC) is a deadly cancer with estimated incidence
of 41.2 per 100,000 people and an incidence in those 65 years of age and older
of 238.1 per 100,000 people.1 While mortality rates have improved since 1975,
the 5-year relative survival is estimated to be only 24.2% for all stages of
disease [(Surveillance, Epidemiology, and End Results (SEER) Summary Stages)]
and only 60.1% for localized disease, the least advanced stage of disease.1

Consensus guidelines recommend surgical resection for medically operable NSCLC
due to research finding that this mode of therapy gives the greatest chance of
cancer survival.2 As with many cancers, adjuvant chemotherapy is a possible
treatment following resection, and a meta-analysis pooling a number of high
quality studies showed that the cisplatin adjuvant treatment tends to improve
survival in patients with NSCLC with the benefit being more pronounced in
those who have a higher risk disease based on a prior version of AJCC staging
criteria.3 Notably, within this meta-analysis adjuvant chemotherapy was not
found to improve overall or disease free survival among those with early stage
NSCLC, particularly Stage IA NSCLC. Risk grouping based on AJCC staging
criteria has remained the basis of identifying groups of patients with NSCLC
for selection of treatment intensity,2 and AJCC staging criteria have evolved
in recent years.

Consensus guidelines from the National Comprehensive Cancer Care Network for
the management of NSCLC recommend consideration of chemotherapy for patients
with Stage IB and Stage IIA cancer based on the most recent (eight edition)
AJCC staging information.2 For Stage IA cancer, chemotherapy is not a
recommendation. For Stages IB and IIA cancer, adjuvant chemotherapy is
recommended to be considered, particularly for patients with additional high
risk clinical or pathological factors. For medically operable higher stage
disease, adjuvant chemotherapy, in addition to possible radiation, is
recommended without further qualification. Notably, in 2017 the American Joint
Committee on Cancer released the eighth edition of staging information for
NSCLC, which redefined T1a tumors as no longer being tumors < 2 cm, but
specifically tumors < 1 cm. The importance of this is that each centimeter of
size is associated with increased risk, and tumors smaller than 1 cm have a
lower risk than those of 1-2 cm.4

While clear clinical and pathologic staging approaches have been developed to
risk stratify patients and clear treatment guidelines-based risk strata have
been published to guide management based on risk strata, disease recurrence is
common. One large retrospective study of patterns of disease recurrence in
early-stage patients was undertaken at a single large academic center.5 The
study reviewed the records of patients who underwent surgery for T1 and T2 and
N0 and N1 NSCLC patients and looked for evidence of recurrence in the medical
record. Records of 975 patients were reviewed, the majority of whom had Stage
IA (45%) or Stage IB (39%) disease. Nearly all patients (96%) had negative
surgical margins. Adjuvant chemotherapy was used in 7% and radiation treatment
was used in 3%. The rate of local recurrence in this cohort was 23%, and the
rate of distant recurrence was 34%, suggesting that disease recurrence is
common even among patients with localized margin-negative disease classified
as low risk based on available clinical and pathologic data. More recent data
from the Surveillance, Epidemiology, and End Results database, shows that even
among those patients with localized disease, 5-year survival rates are at
around 60%.1

**Molecular Risk Stratification**

The frequent recurrence of NSCLC following resection in patients classified as
low-risk based on clinical and pathologic data motivated the development of a
molecular classifier that might be able to more accurately identify which
patients are likely to have disease recurrence or metastatic disease.

The Razor 14-Gene Lung Cancer Assay is a quantitative polymerase chain
reaction (PCR) analysis designed to be used on formalin-fixed, paraffin
embedded lung cancer tissue. The test relies on an algorithmic interpretation
of the quantitative PCR data on RNA from 11 cancer-related target genes (BAG1,
BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR, WNT3A) and 3
reference genes (ESD, TBP, YAP1).

A study by Kratz and colleagues briefly describes the development of the test
and describes clinical validation of the test's predictive ability in two
additional cohorts.6 The test and algorithmic interpretation were developed
using a training cohort of 361 non-squamous resected samples at a single
academic medical center. The test was then validated in samples from 433
patients with Stage I disease from hospitals in the Kaiser Permanente Northern
California system by Kaiser Permanente Division of Research (KPDOR). Another
large-scale validation was done on a cohort of 1006 Chinese patients treated
at institutions participating in the China Clinical Trials Consortium (CCTC).
In the validation components the biopsy samples were sent to a laboratory and
data was analyzed by researchers who were blinded to patient outcomes. A risk
class of low, intermediate, or high risk was assigned to each biopsy prior to
outcome data being released. The investigators studied overall survival in
relation to risk score as the primary outcome, and lung-cancer specific
mortality in relation to the risk score as a secondary outcome. In the KPDOR
Cohort the mean age was 66.6 years with a median of 106 months of survivor
follow-up. The 5-year mortality rate (time post-resection) was 43%. The
majority of cases (77%) were adenocarcinoma. The KPDOR cohort was strictly
Stage I cancers, of which 68% were Stage IA. In the CCTC cohort the mean age
was 58.3 years with a median of 53.4 months of survivor follow-up. The 5-year
mortality rate (time post-resection) was 42%. The majority of cases (88%) were
adenocarcinoma. This cohort contained patients with Stages I, II, and III
disease; 47% had stage I disease (24% stage IA and 23% Stage IIA), 22% had
stage II disease (7% had Stage IIA disease and 15% had Stage IIB disease), and
26% had stage III disease.

In summary, this initial clinical validation study showed that there were
significant differences in overall and cancer-specific survival between
molecular classifier risk strata, even among AJCC Stage I patients in the
KPDOR cohort. The estimated overall 5-year survival based on molecular risk
group for all patients in the KPDOR cohort was 71.4% in the low-risk group,
58.3% in the intermediate-risk group, and 49.2% in the high-risk group. The
estimated 5-year lung-cancer specific survival based on molecular risk group
for all patients in the KPDOR cohort was 84.6% in the low-risk group, 70.3% in
the intermediate-risk group, and 63.3% in the high-risk group. The estimated
overall 5-year survival based on molecular risk group for all patients in the
CCTC cohort was 74.1% in the low-risk group, 57.4% in the intermediate-risk
group, and 44.6% in the high-risk group.

A subsequent study evaluated the ability of the Razor 14-Gene Lung Cancer
Assay to identify high risk disease particularly in small node-negative
disease from the above cohorts.7 In 2012 (prior to the publication of the new
AJCC staging information), the authors addressed the issue of whether the
assay accurately risk stratifies patients with small tumors, including a
subset analysis of tumors < 1 cm. While this group was only 26 patients, they
found that risk stratification based on the assay was associated with
statistically significant differences in 5-year survival.8

Following the development of the assay and retrospective validation studies,
the ability of the test to differentiate early recurrence was prospectively
studied in a study of 52 patients with non-squamous NSCLC.9 The average age
was 62 years, with a mean tumor size of 3.23 cm. The study was mostly Stage I
patients; 25 Stage IA, 15 Stage IB, 7 Stage IIA, 2 Stage IIB, and 2 Stage
IIIA. The median disease-free interval was 10.3 months, and the median lung-
cancer specific survival was 10.3 months. Overall mortality was 8%. No
recurrences or lung-cancer specific deaths were observed in the low or
intermediate risk groups. The recurrence rate was 29% in the high-risk group
with a lung-cancer specific mortality of 14% in this group.

A more recent observational prospective study using the Razor 14-Gene Lung
Cancer Assay in a slightly larger single institution cohort has recently been
published.7 In this study, 100 consecutive patients with stages IA, IB, and
IIA disease treated with a surgical resection between 2011 and 2015 received
molecular testing for risk stratification. The sample had a median age of 67.5
years and was composed of 58 Stage IA patients, 32 Stage IB patients, and 10
Stage IIA patients. The treating clinicians were made aware of the results of
the molecular classification results, though the decision of whether or not a
patient received adjuvant chemotherapy was individualized to the patient.
There were 52 patients stratified as molecular low-risk, and 48 stratified as
molecular high risk, which for this study included both intermediate and high-
risk classifications. No patients with molecular low-risk disease were given
adjuvant treatment. The 5-year disease free survival was 93.8% among those
with molecular low-risk disease and 91.7% among those with molecular high-risk
disease treated with adjuvant chemotherapy. For those with molecular high-risk
disease not treated, the 5-year disease-free survival was 48.9%.

A study on physician use of the test obtained data from 58 physicians who
treated 120 Stage I or II NSCLC patients.10 The study showed that physicians
tended to change management recommendations with regard to the use of
chemotherapy (p < 0.001 for all patients). There was no significant change
between pre- and post-test recommendations for low-risk molecular disease (p =
0.999) or intermediate risk molecular disease (p = 0.146). There was a
significant change particularly in the high molecular risk group (p < 0.001)
with a recommendation to treat 26 of 54 patients with chemotherapy based on
pretest information and 44 of 54 patients with chemotherapy based on post-test
information.

**Level of Evidence**  
Quality: Moderate  
Strength: Limited  
Weight: Limited

Numerous prior Medicare coverage decisions have considered the evidence in the
hierarchical framework of Fryback and Thornbury11 where Level 2 addresses
diagnostic accuracy, sensitivity, and specificity of the test; Level 3 focuses
on whether the information produces change in the physician's diagnostic
thinking; Level 4 concerns the effect on the patient management plan and Level
5 measures the effect of the diagnostic information on patient outcomes. To
apply this same hierarchical framework to analyze an in vitro diagnostic test,
we utilized the ACCE Model Process for Evaluating Genetic Tests.12 The
practical value of a diagnostic test can only be assessed by taking into
account subsequent health outcomes. When a proven, well-established
association or pathway is available, intermediate health outcomes may also be
considered. For example, if a particular diagnostic test result can be shown
to change patient management and other evidence has demonstrated that those
patient management changes improve health outcomes, then those separate
sources of evidence may be sufficient to demonstrate positive health outcomes
from the diagnostic test.

For patients with medically operable NSCLC, surgical resection is a well-
accepted treatment, possibly in conjunction with adjuvant chemotherapy with a
platinum-based combination and / or radiation in patients with higher risk
disease. In consensus guidelines for patients in the lowest risk disease
classification, observation only is recommended following surgery. For
patients with higher risk disease chemotherapy possibly with radiation is
recommended. Current NCCN guidelines rely on clinical and pathologic risk
stratification tools, primarily the AJCC schema; molecular markers of risk are
not considered in these treatment guidelines. Moreover, evidence shows that
even among patients with low-risk disease based on clinical and pathologic
features, recurrence is common, and that outcomes for those who are likely to
have recurrence can be improved in lung cancer with the use of platinum-
containing chemotherapy regimens. However, since platinum-containing
chemotherapy regimens do not improve survival and may negatively impact
survival among lower risk patients, accurate discrimination of those with low
from those with high-risk disease is critical to successfully improving the
outcomes of patients with the use of this treatment. As such, a molecular
classifier that can accurately predict who will have disease recurrence or
metastatic disease among patients already considered low risk for these
outcomes by clinical and pathologic criteria could be used as a decision tool
to improve outcomes by helping to determine who is an appropriate candidate
for platinum-containing adjuvant treatment so as to improve survival.

Observational evidence has shown that molecular risk stratification with the
Razor 14-Gene Lung Cancer Assay enhances risk-stratification among patients
with tumors considered low-risk based on clinical and pathologic criteria.
Since treatment intensity, particularly the decision as to whether or not to
pursue adjuvant chemotherapy is based on risk grouping, the information
provided by the test provides incremental information that can inform
physician management so as to improve outcomes. Furthermore, early
observational prospective evidence suggests that adjuvant chemotherapy given
to patients who do not have a low molecular risk improves disease-free
survival to be similar to those with molecular low-risk disease.