CLINICAL NEWS
Literature Scan
New and noteworthy research from the
medical literature landscape
Clone Wars: Catching Cancer Before it Starts?
A pair of studies recently
published in The New England
Journal of Medicine have uncovered an easily detectable “premalignant” state in the blood critical
to the development of blood
cancer. Taking two different approaches, both research groups
arrived at the same conclusion:
somatic mutations present in
blood cancers leading to clonal
hematopoiesis are rare in younger patients but increase in frequency with age and occur in at
least 10 percent of older patients.
Individuals with these mutations
were over 10 times more likely to
go on to develop blood cancer in
subsequent years.
While most genetic research
has focused on advanced cancers,
the two new studies – one from
Siddhartha Jaiswal, MD, PhD,
and colleagues, and the other from
Giulio Genovese, PhD, and colleagues – looked instead at somatic
mutations in DNA samples collected from the blood of individuals not known to have cancer or
blood disorders.
Dr. Jaiswal and co-authors
looked specifically at 160
genes known to be recurrently
mutated in blood malignancies,
using genetic data from more
than 17,000 blood samples. They
detected mutations in 746 persons (4.3%), affecting 73 genes;
the majority of the variants
occurred in three genes: ASXL1,
DNMT3A, or TET2. These
mutations did indeed increase
the likelihood of developing
blood cancer (hazard ratio [HR]
= 11.1; 95% CI 3.9-32.6), as well
as all-cause mortality (HR=1.4;
95% CI 1.1-1.8), incident
coronary heart disease (HR=2.0;
95% CI 1.2-3.4), and ischemic
stroke (HR=2.6; 95% CI 1.44.8). Jaiswal et al. also observed
a clear association between
age and the frequency of these
somatic mutations: occurring at
a rate of 5.6 percent in persons
aged 60 to 69 years and increasing to a rate of 18.4 percent in
persons 90 years or older.
In the related paper, Dr. Genovese and co-authors discovered the
“precancerous” state when looking
at a different disease: the risk for
schizophrenia. Analyzing data
from whole-exome sequencing of
DNA in blood samples from 12,380
persons (6,135 with psychiatric disorders and 6,245 healthy controls),
the researchers found similar frequencies of age-dependent clonal
hematopoiesis and predominant
mutations in the same genes identified by Jaiswal et al. After following
the medical histories of subjects
with somatic mutations, researchers found that these persons had an
almost 13-fold greater risk of subsequently developing a blood cancer
(HR=12.9; 95% CI 5.8-28.7).
“Cancer is the end stage of
the process,” said Dr. Jaiswal,
from Massachusetts General
Hospital. “By the time a cancer
has become clinically detectable it has accumulated several
mutations that have evolved
over many years.” While there
are no treatments currently
available that would address this
condition in otherwise healthy
individuals, the discovery of
these somatic mutations opens
the door to entirely new directions for blood cancer research
– toward early detection, and
even early prevention. ●
Reference
• Genovese G, Kahler AK, Handsaker RE, et al. Clonal
hematopoeisis and blood-cancer risk inferred from blood
DNA sequence. N Engl J Med. 2014 November 26. [Epub
ahead of print]
• Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal
hematopoiesis associated with adverse outcomes. N Engl J
Med. 2014 November 26. [Epub ahead of print]
Many Younger Patients Receive Inappropriate
First-Line Care
Nearly one-third of adolescent and
young adult patients diagnosed
with cancer do not receive appropriate therapy, according to recent
research published in the Journal
of the National Cancer Institute.
The study highlights inconsistencies in treatment for younger
patients, which could potentially
lead to lower survival rates and
toxicities – particularly for the
44 percent of patients with acute
lymphocytic leukemia (ALL) who
fail to receive appropriate care.
“There has been little improvement in the survival of adolescent
and young adult cancer patients
relative to other age groups in recent decades, raising the question
of whether such patients receive
appropriate initial treatment,”
said Arnold Potosky, MD, first
author of the paper and director
of Health Services Research at
Georgetown University Medical
Center in Washington, DC.
22
ASH Clinical News
To investigate whether initial
cancer treatment could be a factor in these lagging results, Dr.
Potosky and authors reviewed
registry data, patient surveys,
and detailed medical records of a
population-based sample of 504
adolescents and young adults (age
range, 15-39 years). Patients had
ALL, Hodgkin or non-Hodgkin
lymphoma, germ cell cancer, or
sarcoma. “Appropriate” treatment
was defined as the most favorable treatment modality based on
cancer type, tumor node metastasis staging, and other pathologic or
histological characteristics.
Approximately 75 percent of
young cancer patients in this sample received appropriate treatment;
this number dropped to 68 percent
when male patients with stage I
germ cell cancer were excluded – all
of whom received appropriate treatment. Rates of appropriate treatment varied across cancer type:
• 79 percent in sarcoma
• 73 percent of non-Hodgkin
lymphoma
• 58 percent in Hodgkin
lymphoma
• 56 percent in ALL
Among the 27 ALL patients in
the study population, the most
common factor in inappropriate
treatment was failure to receiv e
cyclophosphamide or high-dose
cytarabine as part of consolidation
or maintenance therapy. Physicians may be inadvertently providing inappropriate care because of
their desire to balance benefit of
these combination chemotherapy
regimens against potential toxicity,
the investigators suggested.
Multivariable analysis showed
that only two factors were
significantly associated with the
likelihood of receiving appropriate
treatment: cancer type (p<0.01)
and clinical trial participation
(p=0.04), with patients participating in research having 2.6-times
greater odds of receiving appropriate treatment (95% CI 1.1-6.4).
Despite this benefit, only 7 percent of patients were confirmed to
be participating in clinical research
– although 13 percent of patients
self-reported participation.
While the number of patients
in the current study is small, the
results shine a light on the appropriateness of therapy in younger
cancer patients who fall between
the cracks of pediatric and medical
oncology. Future studies need to
look at the impact of inappropriate
initial treatment on subsequent patient outcomes, including survival,
symptoms, and quality of life, Dr.
Potosky concluded. ●
Reference
• Potosky AL, Harlan LC, ALbritton K, et al. Use of appropriate initial treatment among adolescents and young adults
with cancer. J Natl Cancer Inst. 2014;106:dju300.
Continued on page 27
January 2015