Evolving Early Detection Modalities in Lung Cancer Screening

It would seem intuitively obvious that early detection efforts
of a lethal disorder such as lung cancer would increase the
chances for cure of that disease for individuals, and therefore,
the population from which they derive, and thereby lead to a
reduced death rate (reduced mortality) from that disease. This
has proven to be the case for cervical and breast cancer screening.
1,2 However, to date, no molecular nor imaging modality
of the lung, although suggestive, has yet been sufficiently
evaluated to incontrovertibly confirm that it reduces mortality
for early lung cancer detection. 3 Several studies of various
lung imaging and other modalities are currently under way, are
promising, and are described elsewhere in this textbook (see
Chapters 15 to 17).
The lung is a visceral organ; therefore, access is necessarily
limited. It is virtually impossible to directly examine all ramifications
of the complex branching structures of the bronchial
tree by external imaging, endobronchial fiberoptics, or other
modalities. Therefore, certain aspects of a transforming epithelium
must go unexamined, even by the most sophisticated
sampling techniques. This inherent problem is reflected in
imperfect sensitivity for all molecular lung cancer–screening
modalities tested to date. Clearly, lung epithelial sampling approaches
are evolving.
Also underappreciated is that any given screening modality
will necessarily be imperfectly specific, in isolation, but
two or more complementary stages in screening may, when
coupled, offer vast improvements in predictive value of a positive
test. That is, serial molecular monitoring for risk stratification
could complement or even leverage imaging approaches
to disease detection, by allowing enrichment of the disease
prevalence (“risk”) of the population destined for disease detection
by more specific imaging approaches. Thus, in a typical
population of otherwise unselected middle-aged smokers
and ex-smokers, where lung cancer prevalence is about 2%,
the positive predictive value (PPV) of a noncalcified nodule
detected on spiral computed tomography (CT)—where typically
specificities are 90%—proves to be lung cancer in
only about 18%. 4 However, if one uses a biomarker of risk to
identify a higher-risk portion of the population, where prevalence
for lung cancer is 20%, the PPV (probability that same
CT-detected nodule represents lung cancer in this context), is
much greater at 70%.
Therefore, a staged approach to screening, first using a risk
assessment tool, followed by a disease detection tool, implies
that two different tiers or levels of performance can, when coupled,
have synergistic effects on early detection efficacy. Here,
the first tier of screening would identify less deterministic “risk
factors,” perhaps both demographic and molecular. Such nondeterministic
but informative risk-assessment tools abound in
the literature but are often underappreciated as such. Then, the
second tier testing would entail much more stringent, and specific,
conventional performance criteria for actual lung cancer
detection markers or imaging features. 4
Candidate noninvasive risk assessment tools for lung cancer
screening might simply collect readily available clinical information
in sophisticated risk prediction models. 5,6 Alternatively, as
will be demonstrated, one can biologically sample the entire, or
portions of, lung epithelium and include, for example, germline
genetic polymorphisms in carcinogen metabolism or DNA repair
genes (blood- or buccal cell–based); blood-based proteomic
signatures; transcriptional signatures in a related airway specimen
(e.g., brush-exfoliated buccal cells), sputum oncogene mutation,
or tumor suppressor gene silencing (spontaneously exfoliating
lung epithelial and inflammatory cells); or exhaled breath tests
of volatile (alkanes or aldehydes) or nonvolatile compounds
(DNA), derived from as yet undetermined airway origin (e.g.,
bronchial or alveolar lining fluids).
Conventional clinical disease detection tools might include
anatomic-based CT scans, functional imaging such as positron
emission tomography (PET) scans (see Chapter 27), various
conventional and enhanced optical bronchoscopic techniques
(see Chapters 19 and 28), or other localizing modalities, all
discussed elsewhere in this text, followed by definitive tissue
sampling where indicated, with attendant conventional or
newer molecular assays applied. In this chapter, we will largely
emphasize less invasive, molecular-oriented approaches to both
risk assessment and disease detection that are inherently more
easily applied to an asymptomatic population determined by
clinical history to have some propensity to lung cancer.