Bode, Ann M.

Dong, Zigang

EBioMedicine

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EBioMedicine 11 (2016) 17–18
Contents lists available at ScienceDirect
EBioMedicine
j ourna l homepage: www.eb iomed ic ine.comCommentaryFour Is Better Than 1—Strength in Numbers!Ann M. Bode Ph.D. ⁎, Zigang Dong M.D., Dr. P.H.
The Hormel Institute University of Minnesota, 801 16th Ave N.E., Austin, MN 55912, United StatesDOI of original article: http://dx.doi.org/10.1016/j.ebio
⁎ Corresponding author.
E-mail addresses: ambode@hi.umn.edu (A.M. Bode), z
http://dx.doi.org/10.1016/j.ebiom.2016.08.046
2352-3964/© 2016 The Authors. Published by Elsevier B.Va r t i c l e i n f oArticle history:
Received 30 August 2016
Accepted 30 August 2016
Available online 31 August 2016
20%, a total of 96.4% of the positive screening results in the LDCR
group and 94.5% in the radiography group were false positive results
(National Lung Screening Trial Research et al., 2011). The large percent-
age of false positive results might be reduced by the development of
noninvasive complementary biomarkers.
The identiﬁcation of lung cancer biomarkers that can discriminateThe Center for Disease Control reported that more men and women
in the USA die from lung cancer than any other type of cancer (Siegel et
al., 2016). In 2013, 111,907men and 100,677women in the USwere di-
agnosed with lung cancer and 85,658 men and 70,518 women died
from the disease (Siegel et al., 2016). The lung cancer 5-year survival
rate is about 17.8%, which is lower than the othermajor cancers, includ-
ing colon, breast and prostate (Howlader et al., 2013). Survival rate is
about 54% when the cancer is localized to the lungs; but, unfortunately,
only about 15% of lung cancers are diagnosed before metastasizing to
other organs, which reduces survival to approximately 4% (Howlader
et al., 2013). Furthermore, around 50% of lung cancer patients diewithin
1 year of diagnosis (Howlader et al., 2013). Early diagnosiswould clearly
improve prognosis, but detection is plagued by the lack of speciﬁc, reli-
able diagnostic methods.
Biomarkers are quantiﬁable measurements of homeostasis that dis-
criminate between what is normal versus what is not. Lung cancer is
generally categorized histologically as small cell lung cancer (SCLC;
15% of all lung cancers) or non-small cell lung cancer (NSCLC; 85% of
all lung cancers), with 3 subtypes of NSCLC that include adenocarcino-
ma, squamous cell lung carcinoma, and large cell carcinoma. Cancer bio-
markers should be able to predict lung cancer risk, but most
importantly, should serve as diagnostic tools to detect cancer at the ear-
liest possible stage. Early detection is key to treatment efﬁcacy and over-
all survival. Ideally, effective biomarkers should guide treatment by
changing e.g., expression in response to treatment thereby serving as
a clinical endpoint.
The 2011 National Lung Screening Trial (NLST) assessed the risks
and beneﬁts of low-dose computerized tomography (LDCT) scans com-
pared with chest radiographs to detect lung cancer in 53,000 current or
former heavy smokers (National Lung Screening Trial Research et al.,m.2016.08.018.
gdong@hi.umn.edu (Z. Dong).
. This is an open access article under2011). Although the results indicated a decreased mortality rate of
between normal, benign andmalignant conditions could enable the de-
velopment of more effective diagnostic tools for lung cancer. Circulating
biomarkers in blood have been extensively examined for screening and
diagnosis, and include proteins, microRNA, RNA, circulating cell-free
DNA, methylated DNA, various metabolites, carbohydrates, autoanti-
bodies, lipids, and circulating tumor cells. Common serum biomarkers
utilized for lung cancer detection include cytokeratin 19 fragments
(CYFRA 21-1), carcinoembryonic antigen (CEA), and progastrin-
releasing peptide (ProGRP), but have not always exhibited consistent
reproducibility, sensitivity or speciﬁcity.
Developing multiple biomarkers to be used simultaneously, rather
than a single biomarker, might be a more rational approach because of
the low sensitivity and speciﬁcity of a single biomarker. This is exactly
the approach taken by Ma et al. (2016–in this issue) who identiﬁed
and tested a panel of 4 serum proteins as biomarkers to predict lung
cancer. Their objectivewas toﬁrst identify a robust subset of biomarkers
to distinguish lung cancer patients from normal cancer-free subjects.
They evaluated 20 circulating proteins and identiﬁed 3 proteins, C-reac-
tive protein (CRP), prolactin and hepatocyte growth factor (HGF) that
differed signiﬁcantly between lung cancer patients and normal subjects.
The 4th biomarker chosen was the circulating autoantibody against
cancer-testis antigen NY-ESO-1, which had previously been shown to
differentiate lung cancer patients from healthy subjects (Jia et al.,
2014). Each of the 4 biomarkers (CRP (Chaturvedi et al., 2010), prolactin
(Bigbee et al., 2012), HGF (Tanaka et al., 2011), and NY-ESO-1 (Tureci et
al., 2006)) has been reported as a single biomarker for lung cancer but
had never been combined as a panel until now.
Gender, age and smoking status did not correlate with the 4-bio-
marker results suggesting an independent associationwith lung cancer.
In addition, the biomarkers seemed to be equally accurate for detecting
either SCLC or NSCLC. CEA (carcinoembryonic antigen) was used as a
positive control andwas also higher in serum from lung cancer patients
compared to healthy subjects. However, the 4-marker panel was supe-
rior in AUC (area under the curve), sensitivity and speciﬁcity compared
to CEA. Notably, in a blinded test on patients with suspicious pulmonary
nodules, the adjusted predictionmodel correctly discriminated patientsthe CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
18 A.M. Bode, Z. Dong / EBioMedicine 11 (2016) 17–18with 86.96% sensitivity and 98.25% speciﬁcity. Importantly, the 4-mark-
er panel could detect lung cancer in CEA-negative patients, especially
those with early-stage disease and adding CEA to the 4-marker panel
also increased diagnostic accuracy.
The signiﬁcance of these ﬁndings is that because of the high speciﬁc-
ity, this panel of biomarkers might be suitable for detecting lung cancer,
and especially early stage disease, increasing potential survival and
directing the physician and patient in treatment decisions. This panel
could also be useful to guide CT scanning to accurately identify and clas-
sify other pulmonary abnormalities. Thus, this panel of biomarkers
could dramatically reduce patient anxiety and cost of additional testing,
which would beneﬁt everyone, including the general public.
Although numerous biomarkers have been identiﬁed, validated and
tested in clinical trials, lung cancer is still the most prevalent cancer in
the U.S. Technological advances are needed to improve the detection
of low abundant lung cancer biomarkers that are speciﬁc to lung cancer
subtypes. Combining the use of these 4markers is clearly a step forward
in the detection of lung cancer. On the other hand, the authors indicate
that even though the panel of biomarkers is very promising, the results
are still preliminary. Indeed, the continued successful development of
this panel of 4 lung cancer biomarkerswill entail their complete analysis
in large (i.e., thousands) sets of clinical samples and patients, which
might include other cancer types and other lung diseases, such as in-
ﬂammation, chronic obstructive pulmonary disease, emphysema, pneu-
monia, or asthma, to verify that these markers are speciﬁcally detecting
lung cancer. Importantly, this studywas conducted only in Chinese lung
cancer patients and would need to be expanded to other populations,
including non-Hispanic black men and women, who are more likely to
die from lung cancer than any other racial or ethnic group (Society,
2015). Compared to Asian/Paciﬁc Islanders, who are least likely to die
from cancer, the death rate in blacks is about double (Society, 2015).Disclosure
Authors have nothing to disclose.References
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Four Is Better Than 1—Strength in Numbers! 

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Four Is Better Than 1—Strength in Numbers!

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