1. JNCI Journal
DOI: 10.1093/jnci/djr094 of the National Cancer Institute Advance Access published March 24, 2011 2011.
Published by Oxford University Press
For Permissions, please e-mail: journals.permissions@oup.com.
COMMENTARY
Unique Characteristics of Adolescent and Young Adult Acute
Lymphoblastic Leukemia, Breast Cancer, and Colon Cancer
James V. Tricoli, Nita L. Seibel, Donald G. Blair, Karen Albritton, Brandon Hayes-Lattin
Manuscript received March 23, 2010; revised February 18, 2011; accepted February 18, 2011.
Correspondence to: James V. Tricoli, PhD, Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 6130
Executive Blvd, Executive Plaza North, Rockville, MD 20852 (e-mail: tricolij@mail.nih.gov).
Each year in the United States, nearly 70 000 individuals between the ages of 15 and 40 years are diagnosed with cancer.
Although overall cancer survival rates among pediatric and older adult patients have increased in recent decades, there has
been little improvement in survival of adolescent and young adult (AYA) cancer patients since 1975 when collected data
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became adequate to evaluate this issue. In 2006, the AYA Oncology Progress Review Group made recommendations for
addressing the needs of this population that were later implemented by the LIVESTRONG Young Adult Alliance. One of their
overriding questions was whether the cancers seen in AYA patients were biologically different than the same cancers in adult
and/or pediatric patients. On June 9–10, 2009, the National Cancer Institute (NCI) and the Lance Armstrong Foundation (LAF)
convened a workshop in Bethesda, MD, entitled “Unique Characteristics of AYA Cancers: Focus on Acute Lymphocytic Leukemia
(ALL), Breast Cancer and Colon Cancer” that aimed to examine the current state of basic and translational research on these
cancers and to discuss the next steps to improve their prognosis and treatment.
J Natl Cancer Inst 2011;103:1–8
One reason that there has been less progress in treating cancers among pediatric ALL patients vary depending on the presence of
among adolescents and young adults might be that the biology is various recurring cytogenetic abnormalities. ALL patients with
different from the same diseases in younger and older individuals. “good” prognosis cytogenetics (such as trisomies of chromosomes
The Progress Review Group on adolescent and young adult (AYA) 4, 10, or 17, or t(12;21)/TEL-AML1) had relatively high survival
oncology recommended that we improve the “understanding of rates, whereas those with other recurring abnormalities had inter-
host/patient biology of aging and cancers, including sarcomas, mediate or poorer outcomes (1). Substantial differences existed in
leukemias, lymphomas, and breast and colorectal carcinomas” and the frequencies of various cytogenetic abnormalities among AYA
investigate a “potential biological basis of age-related differences patients compared with younger ALL patients, including a precip-
in outcome for AYA cancers.” As a result, the Bethesda workshop itous decline in the frequency of the “good prognosis” abnormal-
was organized to review and update the status of AYA research in ities by approximately 20 years of age. The “poor prognosis”
these cancers and to consider whether there is sufficient evidence abnormalities, such as t(9;22)/BCR-ABL, were more common
for a unique biology in these AYA cancers to distinguish them in AYA ALL (2). Under the auspices of the National Cancer
from the adult and (in the case of acute lymphocytic leukemia Institute’s (NCI’s) Strategic Partnering to Evaluate Cancer
[ALL]) pediatric versions of the disease. We hoped to gain a better Signatures (SPECS) program and its Therapeutically Applicable
understanding of AYA cancers and to identify new therapeutic Research to Generate Effective Treatments (TARGET) project,
targets and treatment approaches for AYA patients. Willman and colleagues recently completed gene expression pro-
filing studies to identify and characterize novel genetic abnormal-
ities and therapeutic targets in a cohort of 207 older children with
AYA Acute Lymphoblastic Leukemia “high-risk” ALL (mean age = 13.5 years, with white blood cell
Acute lymphoblastic leukemia is one of the leading causes of can- counts higher than 50 000/mm3 at presentation) who had been
cer-related deaths among adolescents and young adults. Overall treated on the Children’s Oncology Group (COG) 9906 protocol.
survival and disease-specific survival of ALL are clinically signifi- Gene expression clustering algorithms revealed eight gene expres-
cantly poorer in AYA patients than in children between 1 and 10 sion cluster groups, two of which were associated with distinct
years of age. It is not known whether these outcome differences are cytogenetic abnormalities [11q23 rearrangements MLL or t(1;19)
due to distinct genetic and biological features, different thera- E2a-PBX1] and six of which were entirely novel, in which the un-
peutic regimens and intensities, differences in compliance to derlying genetic abnormalities were unknown. One of the novel
therapy, or other social and behavioral issues (Table 1). clusters, which represented 12%–15% of all high-risk ALL cancers
Dr Cheryl Willman (University of New Mexico Cancer studied in this series, was characterized by high expression of
Research and Treatment Center) discussed evidence that outcomes CRLF2, GPR110, MUC4, and other genes associated with activated
jnci.oxfordjournals.org JNCI | Commentary 1

2. Table 1. Special features of cancers in adolescent and young adult (AYA ) patients
Features of acute lymphocytic leukemia in AYA patients compared with children
Higher incidence of poor prognostic cytogenetic features such as t(9;22) (Philadelphia Chromosome) or hypodiploidy
Lower incidence of favorable cytogenetic features associated with a favorable outcome such as high hyperdiploidy and t(12;21) ETV6-RUNX1
translocation
More likely to be associated with aberrant gene promoter methylation
Features of breast cancer in AYA patients compared with adults
Lower survival rate
Worse outcome independent of stage, extent, or type
Higher incidence of more aggressive triple-negative form
More likely to be higher grade, poorly differentiated, and less hormone-sensitive
More frequent spread to greater number lymph nodes
Features of colorectal cancer in AYA patients compared with adults
More advanced disease and poorer prognosis at diagnosis
Less responsive to treatment
More mucinous histology and greater frequency of signet ring cells
Greater frequency of microsatellite instability
Lower frequency of loss of heterozygosity at 17p and 18q
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tyrosine kinases, and frequent deletions of IKZF1, BTLA/CD300, 5 years, there was a 71% incidence of a recurrence in patients
RAG1-2, and EBF1. It was also associated with Hispanic or Latino harboring both lesions as compared with 18% incidence in
race (P = .001) and with very poor 4-year relapse-free survival patients with neither lesion.
(21%, P < .001) (3–7). Because these gene expression profiles were Although much is known about the genetics of childhood ALL,
characteristic of activated tyrosine kinase pathways, some kinases data are limited for AYA ALL. Dr Christine Harrison (Northern
were resequenced, leading to the discovery of novel Janus kinase 2 Institute for Cancer Research at Newcastle University) described
(JAK2) and other kinase mutations in this high-risk form of the the UK’s Leukaemia Research Cytogenetics Group database,
disease. These studies suggest that perturbation of these signaling which includes cytogenetic information and records of treatments
pathways, along with IKZF1 deletion, cooperate to promote leuke- on 1205 AYA patients, aged 13–24 years (8). Nearly 500 of these
mogenesis. Early phase clinical trials to test JAK inhibitors in patients were treated on adult ALL clinical trials. Analyses of over-
patients with high-risk ALL are ongoing (3). Dr Willman noted all survival and event-free survival (EFS) revealed that AYA
that in preliminary studies, AYA ALL cancers appeared to be ge- patients of the same age had worse outcomes when treated on an
netically similar to high-risk pediatric ALL. Working with the adult ALL protocol vs a pediatric ALL protocol. Of this group of
NCI adult cooperative groups, the TARGET cohort is being ex- patients, 432 were aged 13–14 years, 544 were aged 15–19 years,
panded to include 400 AYA ALL patients (NCI 1RC1 CA145707; and 229 were aged 20–24 years; 63% were young men. Most
Willman and Mullighan, principal investigators). patients had BCP-ALL (79%) and 21% had T-lineage ALL. The
Treatment failure remains a major problem in the management incidence of T-lineage, ALL-specific cytogenetic abnormalities
of pediatric, adolescent, and young adult ALL. The genetic basis varied among children, AYAs, and adults. For example, the
of treatment failure is particularly poorly understood in the AYA CALM-AF10 translocation occurred more frequently in AYAs
population because it often occurs in patients lacking known high- than in children or adults. Of the 837 AYA patients in this group
risk alterations such as MLL-rearrangement or BCR-ABL1. who had BCP-ALL there were more 13–24 year olds with t(4;11)
Dr Charles Mullighan (St Jude Children’s Research Hospital) (q21;q23) translocations (4%) than children aged 1–12 years with
presented the results of an integrated genomic analysis of B-cell pre- the same translocation (2%). Greater than 50% of AYA BCP-ALL
cursor (BCP) samples that lacked known high-risk genetic alter- patients had a visible abnormality of chromosome arm 9p, whereas
ations from a cohort of high-risk pediatric and adolescent ALL other AYA BCP-ALL patients exhibited trisomies of chromosomes
patients (COG P9906 cohort). They identified deletions and point 21, 8, or 5. Trisomy 5 as a sole cytogenetic change has previously
mutations of the lymphoid transcription factor IKZF1 that were been associated with a poor outcome (9). Intrachromosomal am-
associated with a nearly threefold increased risk of relapse (hazard plification of chromosome 21 (iAMP21) has an incidence of about
ratio = 2.40; 95% confidence interval = 1.38 to 4.2). The gene 3% in older children with ALL (median age 9 years) and accounts
expression signatures of these patients were very similar to those of for 5% of AYA (10); it is associated with BCP immunophenotype
BCR-ABL1 ALL patients, and by resequencing, activating muta- and low white blood cell count. Data from the Medical Research
tions of Janus kinases (JAK1, JAK2, and JAK3) were identified in Council ALL97 trial revealed that patients with iAMP21 had very
11% of the cohort. The mutated JAK kinases could transform cells poor EFS and experienced both early and late relapses. However,
in vitro, were responsive to JAK inhibitors, and were associated the overall patient survival was relatively good (5-year EFS was
with very poor outcome when combined with IKZF1 deletions. 29%, whereas overall survival was 71%) following treatment for
When analysis was restricted to the adolescent ALL cases (N = 58; their relapsed disease (11). Currently, these patients are being
16–21 years of age), similar results were found: 50 of these patients treated as at high risk in the Medical Research Council ALL2003
lacked a sentinel chromosomal alteration; however, they had a childhood ALL trial. Other translocations observed in BCP-ALL
high frequency of JAK mutations and IKZF1 deletions, and in involve the immunoglobulin heavy chain locus (IGH@) and are
2 Commentary | JNCI Vol. 103, Issue 8 | April 20, 2011

3. seen more frequently in older children and adolescents as com- Institute) described a pilot study that was initiated to determine the
pared with younger children (12–15). feasibility of administering the Dana-Farber Cancer Institute pedi-
Dr Wendy Stock (University of Chicago) described the chal- atric regimen to young and middle-aged adults between 18 and 50
lenges of treating ALL in the AYA population. Older adolescents years of age (20). Preliminary results suggest that an asparginase-
and young adults with ALL (16–21 years of age) have worse out- intensive pediatric regimen is feasible in older adolescents (aged
comes (7-year EFS = 34%) than children at 1–10 years of age for 15–18 years) and young adults (aged 18–50 years) with ALL.
whom the cure rate now approaches 80%–85%. A retrospective
comparison of 16–20 year olds with ALL who were treated on the
Children’s Cancer Group (CCG) or Cancer and Leukemia Group AYA Breast Cancer
B (CALGB) ALL protocols revealed that despite similar remission Breast cancer is the second most common cause of cancer-related
rates between the two treatment groups, there was a statistically death for women in the United States and is the leading cause of
significantly lower 7-year EFS among those participants treated cancer death for young women aged 15–29 years. Younger women
on the CALGB protocol as well as a higher rate of central nervous with breast cancer exhibit an increased likelihood of recurrence
system relapse (16) (7-year EFS = 63% [CCG AYAs] vs 35% and death compared with older premenopausal women, and young
[CALGB] AYAs; relative incidence ratio = 9.2, 95% confidence age is itself an indicator of poorer survival. Although multiple fac-
interval = 2.0 to 42.7; P < .001). Compared with adult protocols, tors may contribute to these differences, the goal of this Workshop
the pediatric protocols featured substantially more nonmyelosup- was to address the hypothesis that a unique biology may underlie
pressive therapy (vincristine, corticosteroids, and l-asparaginase) the distinctive properties of breast cancer in adolescent and young
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elements and more intensive early CNS-directed therapy. Similar adult women (Table 1).
results have been observed in retrospective analyses of AYA Dr Christopher Benz (Buck Institute for Age Research) noted
patients in France, the United Kingdom, and the Netherlands; that the link between breast cancer and aging is poorly understood
nearly identical remission rates were observed, but EFS and sur- and that late-onset breast cancers are more likely to overexpress
vival were substantially better for AYA patients enrolled on the estrogen receptor (ER)-a and progesterone receptor (PR), whereas
pediatric trials (67% vs 41% 5-year EFS in France; 71% vs 56% breast cancers in women younger than 40 years are more likely
5-year overall survival in the United Kingdom, and 71% vs 38% to be “triple-negative,” lacking overexpression of ER, PR, and
5-year EFS in the Netherlands) (17–19). HER2. Biomarkers like HER2 and Ki-67 are inversely associated
Explanations for these striking differences include potential, with ER expression and appear to be more commonly associated
clinical, and biological differences among adolescents who received with early-onset breast cancer (21).
treatment at pediatric centers compared with adult centers, differ- In studies of differences in gene expression among women of
ences in protocol design and dose intensity, and potential varia- different ages with breast cancer, early-onset ER-positive breast
tions in the degree of adherence to the protocol drug administration cancers were more proliferative and more likely to result in meta-
by medical oncologists and their patients compared with pediatric static relapse compared with stage-matched ER-positive breast
oncologists and by their patients. To address many of these unan- cancers that arose after age 40 years. A comparison of node-
swered questions, the adult cooperative groups are performing a negative breast cancers that were diagnosed in women aged
prospective trial that focuses specifically on AYAs (Intergroup trial 70 years or older with those that were diagnosed in women
C10403). Newly diagnosed ALL patients between ages 16 and 40 younger than age 45 years revealed differences in gene expression
years are eligible for treatment that parallels the current COG microarray profiles but no age-associated genomic differences
study for adolescents and high-risk children (AALL0232). (22). ER-negative breast cancers proliferated faster than
Asparginase, which deprives the leukemic cells of asparagine ER-positive breast cancers and were associated with greater risk of
that is essential for growth, is considered to be part of the standard early metastatic relapse regardless of age at diagnosis. For
treatment in pediatric ALL protocols. However, because of tox- ER-negative breast cancer, better biomarkers are needed to predict
icity and limited tolerability in older adults, medical oncologists do patient outcome and treatment responsiveness, and more studies
not routinely use it. Since 1973, the Dana-Farber Cancer Institute are needed to evaluate the biological heterogeneity of early-onset
ALL Consortium has conducted randomized multi-institutional ER-negative breast cancers in different ethnic populations.
clinical trials for children up to 18 years of age with newly diag- Dr Thea Tlsty (University of California, San Francisco; UCSF)
nosed ALL. Older adolescents (15–18 years old) have been treated emphasized that premalignant breast tissue also exhibits specific
as high-risk, and postinduction consolidation (follow-up therapy molecular subtypes that may give clues to targeting treatment.
after the induction of remission in the patient) has focused on Ductal carcinoma in situ (DCIS) is a nonobligate precursor of in-
continuous asparagine depletion by administration of asparginase vasive breast cancer, and 50% of DCIS patients do not go on to
for 20–30 weeks. Fifty-one patients aged 15–18 years were treated develop invasive cancer. Although DCIS is relatively rare in young
in two consecutive Dana-Farber Cancer Institute ALL Consortium women, the tendency to reoccur is higher in this population. The
trials. Compared with patients aged 1–10 years, older adolescents UCSF DCIS Clinical Cohort Study identified biomarkers in the
experienced more thromboembolic complications (2% in 1–10 lesions of women with DCIS that can predict future diagnosis of
year olds vs 14% in 10–15 year olds vs 10% in 15–18 year olds, invasive breast cancer (23), and a molecular signature in which
P < .01) but had similar rates of pancreatitis and asparginase allergy. high levels of p16 and low levels of Ki67 expression were associ-
The 5-year EFS for these older adolescents was 78%. Based on ated with recurrence-free survival. High levels of p16-regulated
this favorable outcome, Dr Lewis Silverman (Dana-Farber Cancer proliferation markers (E2F and cyclin E1) and cyclooxygenase-2
jnci.oxfordjournals.org JNCI | Commentary 3

4. collectively characterize the basal-like breast tumors that are more Dr Charlotte Kuperwasser (Tufts University School of
frequently seen in younger women, and high cyclooxygenase-2 Medicine) described her human-in-mouse model in which human
and Ki67 expression in basal-like DCIS were associated with a stromal cells, epithelial cells, and primary fibroblasts from a reduc-
high probability of recurrence. Dr Tlsty emphasized the need for tion mammoplasty are used to generate human breast tissues that
specific predictive tests for basal-like DCIS cancers to alleviate organize both structurally and functionally in mice (31,32) and are
women’s anxiety regarding treatment and prognosis that accom- virtually indistinguishable from breast tissue taken directly from
panies this diagnosis. Dr Tlsty also described new studies that humans (33). She also discussed ER-negative breast cancer, its as-
identified rare subpopulations of breast epithelial cells that have sociation with age of breast cancer onset, and the role of estrogen
properties of stem cells or premalignant cells and suggested that in breast cancer formation and progression. Estrogen accelerated
premalignant cells might be good treatment targets in young the growth of ER-negative tumors in a mouse model of preg-
women. nancy-associated breast cancer, and it also accelerated tumor
Dr Carey Anders (University of North Carolina, Chapel Hill) formation by ER-negative human breast, prostate, and colon
explained that although the risk of breast cancer is lower in younger cancer cell lines (34). In mice, estrogen increased angiogenesis—
women, survival of women aged 25–30 years is lower across all increasing the number and size of blood and lymphatic vessels,
subtypes and stages (24). However, risk factors associated with stromal cells, and the incidence of metastasis—and stimulated cells
premenopausal breast cancer (obesity, high caloric intake, seden- in the bone marrow to mobilize to sites of angiogenesis (34).
tary lifestyle, early age at menarche, heavy alcohol intake, high Tumors that arose during times of high circulating estrogens
intake of red meat, and high breast density) are not exclusive to apparently lacked the ability to respond directly to the hormone,
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early-onset breast cancer. Early-onset tumors were associated with suggesting that estrogen may work indirectly to promote cancer in
family history of the disease, a more aggressive phenotype, younger women (34).
ER- and/or PR-negative status, and compared with tumors in women
older than age 30 years, were larger and more often associated with
positive lymph nodes and higher levels of HER2 expression. AYA Colon Cancer
Dr Anders and her collaborators compared gene expression, It has been known for the last two decades that AYA patients with
clinicopathologic features, and oncogenic pathway deregulation in colorectal cancer have a poorer prognosis and more aggressive
more than 700 tumors according to patients’ ages. They confirmed disease than older adults (35). However, the biological basis and
differences in pathology and mRNA expression of ER, PR, HER2, the clinical ramifications of this observation remain incompletely
and the epidermal growth factor receptor (25) and that diagnosis defined. Some of the best evidence that colorectal cancer is biolog-
at an age younger than 45 years was the strongest predictor of poor ically different in AYA patients compared with older adults
prognosis. Compared with tumors in older women, tumors from includes diagnosis at a more advanced tumor stage, greater
young women had multiple clusters of differentially expressed frequencies of mucinous histology, signet ring cells, high microsat-
genes, including a higher probability of phosphatidylinositol-3 ellite instability (MSI-H), and a higher incidence of mutations in
kinase and Myc pathway deregulation (26). Such differences may one of the mismatch repair (MMR) genes that results in its consti-
underlie the clinical and prognostic differences in early-onset tutive expression (36–40) despite some evidence to the contrary
breast cancer. Dr Anders noted that among pre- and postmeno- (41). In addition, there are lower frequencies of KRAS mutations,
pausal women with breast cancer who have been treated similarly, loss of heterozygosity at 17p and 18q, and lower p53 protein levels
younger women with stage I or II cancers are twice as likely to in AYA colorectal tumors (Table 1).
suffer local recurrence following lumpectomy and radiation than Dr Sharon Plon (Baylor College of Medicine) discussed ge-
older women, so there is a need for improved individualized strat- netic susceptibility syndromes that are associated with an increased
egies for both local and systemic therapy for young women. risk of developing colorectal cancer in AYA populations. Familial
Dr Christine Ambrosone (Roswell Park Cancer Institute) adenomatous polyposis is an autosomal dominant condition in
reported that European American women have higher incidence of which polyps can begin to develop in the first decade of life, exten-
breast cancer than African American women, and premenopausal sive polyposis with atypia may be present during the teen years,
women of both races develop a higher proportion of basal-like and frank invasive carcinoma often develops in young adults (42).
tumors than postmenopausal women (27). African American The lifetime cumulative risk of colorectal cancer is virtually 100%
women are more likely than white women to be diagnosed before for familial adenomatous polyposis patients, with a cumulative risk
age 40 years with more aggressive basal-like tumors (28,29). of approximately 50% by age 33. Familial adenomatous polyposis
Data from the Women’s Circle of Health Study (30) con- is caused by the presence of germline heterozygous mutations of
firmed that ER-negative tumors were more common among the APC gene, of which approximately 80% are predicted to trun-
African American women than among white women, particularly cate the APC protein. Approximately 80% of all colorectal tumors
when younger women were compared. Also, regardless of race, exhibit chromosomal instability that is associated with either
women younger than age 40 years were more likely than women inherited or somatic mutation of the APC gene. Chromosome
aged 40 years and older to have high-grade tumors. Genome- instability is less frequently observed in AYA than in adult colo-
wide association studies have suggested that different genes are rectal cancer, and AYA tumors are more likely to exhibit microsat-
associated with breast cancer in African American women com- ellite instability (40).
pared with European American women, but age-stratified data Dr Plon pointed out that hereditary nonpolyposis colorectal
are needed. cancer (HNPCC, also called Lynch syndrome) is an autosomal
4 Commentary | JNCI Vol. 103, Issue 8 | April 20, 2011

5. dominant syndrome without polyposis that is associated with an features noted may contribute to a perceived poorer outcome in
approximately 70% lifetime risk of colorectal cancer (often right- children with colorectal cancer, the markedly higher incidence of
sided) and a 50%–70% risk of endometrial cancer (42). The auto- mucinous and signet ring adenocarcinoma in children suggests
somal dominant form is caused by heterozygous mutations in one that there are potentially important biological differences between
of four MMR genes (MSH2, MLH1, MSH6, or PMS2) and is asso- colorectal cancer in children and adults.
ciated with colon cancer that can appear in patients as young as Dr David Thomas (Peter McCallum Cancer Center) and
their mid-20s as well as in older adults. Silencing of the MLH1 gene Dr Archie Bleyer (Oregon Health and Sciences University) dis-
by methylation is observed in 20% of sporadic colorectal cancer. cussed the published data that have suggested that patients with
Colorectal tumors with MLH1 silencing or from patients with early-onset colorectal cancer are more likely than older patients to
HNPCC demonstrate microsatellite instability. In early-onset co- present with advanced-stage disease, to have mucinous tumors,
lorectal cancer, diagnosis of HNPCC involves testing for MSI or to have poorly differentiated and right-sided cancers, and to have
analysis of MMR protein expression by immunohistochemistry. In a higher proportion of rectal cancers. For patients younger than
very young patients, one should consider the autosomal recessive 30 years, the literature strongly suggests an overall survival disad-
mismatch repair deficiency (MMR-D) syndrome, in which a child vantage. However, it is not clear whether patients younger than
inherits a mutation in the same MMR gene from both parents. The 45 years have worse outcomes than their older counterparts
clinical phenotype includes susceptibility to glioma, leukemia, lym- when stage of disease is taken into account. There may be stage-
phoma, or colorectal cancer in children and young adults (43). independent and age-related outcomes in patients younger than
Colorectal tumors in the AYA population are more often mu- 30 years, suggesting that there may be biological differences in
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cinous and right-sided than in older populations, consistent with cancers that affect the very young. Such biological differences may
the increased prevalence of HNPCC-associated tumors in this be associated with inherited predisposing syndromes or with other
population. Between 80% and 90% of tumors from patients with risk factors, such as inflammatory bowel disease, whose incidence
HNPCC demonstrate MSI, and 90% of colorectal cancers with is greater in younger populations.
MSI have somatic TGFBR2 mutations due to expansion of a repeat Dr Michael LaQuaglia (Memorial Sloan-Kettering Cancer
within the TGFBR2 gene. Up to 30% of all human colorectal can- Center) pointed out that there are few reports of colorectal cancer
cers have mutations in transforming growth factor- (TGF)-b sig- in patients aged 30 years and younger, and most that do exist are
naling–related genes. Dr Thomas Doetschman (BIO5 Institute) case histories or small institutional series. To address this deficit, a
discussed a TGFb1-deficient mouse model that displayed features retrospective multi-institutional review was conducted using a
of human colorectal cancer in that the colon cancer was associated total of 167 patients aged 10–30 years (median age = 21 years) who
with inflammatory lesions, occurred in the cecum and proximal were identified through a survey of COG institutions; of these
colon, and developed into mucinous carcinoma (44). In a Rag22/2 patients, 40% had a family history of colorectal cancer. Tumors
(immunocompromised) background, both TGFb1-deficient and were relatively evenly distributed throughout the colon and rec-
TGFb1-sufficient mice developed premalignant hyperplastic le- tum. Most of the patients presented with stage III or IV disease,
sions with inflammatory infiltrates, but the lesions progressed to and 60% had distant metastases. Very few of these tumors were
mucinous carcinoma in only the TGFb-deficient mice. The well differentiated, with 37% and 55% being poorly and moder-
TGFb1-deficient mouse models have the potential to reveal clues ately differentiated, respectively. Signet ring histology was
regarding disease mechanisms in colorectal cancer that will con- observed in 23% of the tumors and was more commonly seen in
tribute to a better understanding of this disease in AYA patients. younger patients within the cohort. MMR-D was identified via
Dr Ashley Hill (Children’s National Medical Center) cited data immunohistochemistry in 17% of the tumors. With a median of 48
from the Surveillance, Epidemiology, and End Results program months follow-up, median overall survival for this cohort was 44
that suggested that colorectal cancer has a similar natural history months: 88 of 159 patients died. Compared with adult patients, a
in patients aged 15–29 years and in older patients. It has been higher proportion of AYA colorectal cancer patients had stage III
speculated that delayed diagnosis and treatment play a role in the and IV disease and a worse overall prognosis. The proportion of
poorer outcomes observed among AYAs. A retrospective review of tumors with signet ring cell characteristics was also higher but was
77 pediatric colorectal cancer patients showed that the frequency not associated with a difference in survival. Within each age group,
of mucinous adenocarcinoma was considerably higher among chil- patients with MSI tumors demonstrated more favorable outcomes
dren (62%) than among adults (11%–13%). Overall, 86% of than those with microsatellite stable tumors. However, AYA colo-
patients had advanced-stage disease at presentation, with more rectal cancer patients with either MSI or microsatellite stable
than half exhibiting distant metastases. tumors had worse disease-specific survival than their older coun-
Clinical symptoms of colorectal cancer in children mirror those terparts. These data suggested that colorectal cancer among
found in adults and include abdominal pain, weight loss, and patients of this age group was associated with unique clinical and
anemia, but the rarity of colorectal cancer in children compared biological properties.
with other causes of abdominal discomfort often prolongs the
interval from onset of symptoms to diagnosis. In this study, the
length of this interval did not appear to be associated with outcome Statistical Issues in Working With the AYA
because children who presented with an acute onset of symptoms Population
invariably had more advanced stages of disease. Although the lack Dr Lisa McShane (National Cancer Institute) highlighted statis-
of colorectal cancer screening among children and the clinical tical challenges in the molecular characterizations of AYA cancers
jnci.oxfordjournals.org JNCI | Commentary 5

6. and clinical trial design. Key issues include whether AYA cancers differences and their impact on therapy and on protocol adherence
are biologically homogeneous or reflect heterogeneous subtypes, by both physicians and patients. It is crucial to let AYA patients and
and whether they are distinct from pediatric and adult cancers or referring physicians know the importance of treatment at cancer or
merely reflect a shift in subtype distribution. Clinically, it will be academic centers that understand the value of sometimes treating
important to identify prognostic and predictive biological subtypes AYA patients using pediatric rather than adult protocols and can
that relate to disease natural history or predict patient response to provide access to clinical trials. Currently, there are no known
certain therapies and critical to expand and coordinate specimen preventive strategies for ALL.
collections with standardized pathological and clinical data. For breast cancer, the consensus was that there is currently
High-dimensional molecular profiling provides a promising little evidence to prove that AYA breast cancer is biologically
approach to elucidate the biology of AYA cancers and develop in- unique; however, there may be an enrichment of certain breast
formative clinical tools. Unsupervised statistical analysis methods cancer subtypes among this age group and further research is
such as clustering can be used to identify biological subgroups needed. Despite the fact that AYA breast tumors were more ag-
suggestive of therapeutic targets. A variety of supervised analysis gressive and had a less favorable prognosis, there was no consensus
methods are available to construct prognostic or predictive classi- that these tumors should be categorized as high risk based solely
fiers or risk scores (45,46). on AYA age group. It was agreed that we need better sources for
Dr McShane discussed the design of oncology clinical trials well-annotated samples, increased awareness of the need for re-
(47,48). AYA patients may have highly variable biology indepen- search among AYA women with breast cancer, and increased co-
dent of disease, and patient accrual to clinical studies is chal- ordination between groups and institutions.
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lenging. Phase I trials of AYA cancers should include The evidence that AYA colorectal cancers may differ biologically
pharmacokinetic and pharmacodynamic goals because hormonal from those in older populations includes poorer overall survival,
or other biological differences may affect drug dosing and sched- higher prevalence of mucinous tumors, increased chromosome
uling. Single-arm phase II trials may require less than half the stability, and increased rate of MMR-D in AYA colorectal cancer
sample size of some randomized phase II trials to achieve compa- patients. Some of this evidence is anecdotal, and the perception that
rable type I (a) and type II (b) error. However, their reliance on survival rates for AYA patients with colon cancer are lower than
historical benchmarks can be problematic, particularly if AYA those observed in older patients is not supported by existing
cancers represent rare biological subtypes (49). Various random- Surveillance, Epidemiology, and End Results data. However, there
ized phase II trial designs have been proposed for rare cancers: for may be substantial differences in biology and other features between
example, when screening trials are done for preliminary compar- different age groups even within the population of AYA patients
ison of an experimental treatment to the standard regimen, the with colorectal cancer. If age is a good surrogate for a unique tumor
screening design allows for larger type I and II errors and targets a biology associated with AYA cancers, then studies of colorectal
larger effect size than a phase III trial (50), thereby allowing cancer in AYA patients will almost certainly illuminate alternative
smaller sample size than a typical phase III trial. tumorigenic pathways and will also likely benefit patients in other
Phase III trials can be made more efficient by stratifying biolog- age groups whose tumors exhibit similar biological features.
ical subgroups to adjust for variability or enrich for patients most The niche occupied by AYA cancer patients is unique, sitting
likely to benefit from a new therapy. Enrichment designs provide astride a somewhat nebulous dividing line between childhood can-
no information for excluded patient subgroups and require a robust cers and the adult versions of the disease. The immediate steps
assay to identify the targeted subgroup, but they avoid dilution of required to further our understanding of AYA cancers are 1) to de-
treatment effects by patient subgroups thought unlikely to benefit finitively determine whether there are identifiable molecular features
from the experimental therapy. Factorial designs can test multiple of these cancers that distinguish them from the adult and pediatric
treatments in combination so that patients serve “double duty” to versions and 2) to elucidate whether these differences can in some
provide information on more than one treatment, but interpreta- way explain their clinical behavior. Only in this way will we able to
tion can be complicated if treatment interaction effects are present. develop new approaches for identifying targets for AYA cancer
Systematic review and meta-analysis techniques can be used to prognosis and treatment and reduce mortality among this age group.
draw conclusions across a series of studies (51) and could be fruitful
if AYA data can be extracted from previous larger clinical trials.
References
1. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet.
Conclusions 2008;371(9617):1030–1043.
2. Harrison CJ. Cytogenetics of paediatric and adolescent acute lympho-
For all of the AYA cancers discussed, one priority is to ensure the
blastic leukaemia. Br J Haematol. 2009;144(2):147–156.
availability of an adequate number of tissue samples to ascertain 3. Mullighan CG, Zhang J, Harvey RC, et al. JAK mutations in high-risk
whether there are biological differences based on age. For ALL, childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2009;
there has been improved clinical trial participation for AYA 106(23):9414–9418.
patients (eg, CALBG 10403), which should augment tissue 4. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in
acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–480.
collection. Furthermore, funding to investigate the molecular
5. Kang H, Chen IM, Wilson CS, et al. Gene expression classifiers for
differences between pediatric and AYA ALL was secured from relapse-free survival and minimal residual disease improve risk classification
the American Recovery and Reinvestment Act as a result of the and outcome prediction in pediatric B-precursor acute lymphoblastic
workshop. Additional studies are needed on pharmacokinetic leukemia. Blood 2010;115(7):1394–1405.
6 Commentary | JNCI Vol. 103, Issue 8 | April 20, 2011

7. 6. Harvey RC WX, Dobbin KK, Davidson GS, et al. Identification of novel shared patterns of gene expression. J Clin Oncol.
cluster groups in pediatric high risk B-precursor acute lymphoblastic leu- 2008;26(20):3324–3330.
kemia by gene expression profiling: correlation with genome-wide DNA 26. Anders CK, Acharya CR, Hsu DS, et al. Age-specific differences in oncogenic
copy number alterations clinical characteristics and outcome. Blood. pathway deregulation seen in human breast tumors. PloS One. 2008;3(1):e1373.
2010;116(23):4874–4884. 27. Millikan RC, Newman B, Tse CK, et al. Epidemiology of basal-like breast
7. Harvey RC, Mullighan CG, Chen IM, et al. Rearrangement of CRLF2 is cancer. Breast Cancer Res Treat. 2008;109(1):123–139.
associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/ 28. Gapstur SM, Dupuis J, Gann P, et al. Hormone receptor status of breast
Latino ethnicity, and a poor outcome in pediatric B-progenitor acute tumors in black, Hispanic, and non-Hispanic white women. An analysis of
lymphoblastic leukemia. Blood. 2010;115(26):5312–5321. 13,239 cases. Cancer. 1996;77(8):1465–1471.
8. Harrison CJ, Martineau M, Secker-Walker LM. The Leukaemia Research 29. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and
Fund/United Kingdom Cancer Cytogenetics Group Karyotype Database survival in the Carolina Breast Cancer Study. JAMA. 2006;295(21):2492–2502.
in acute lymphoblastic leukaemia: a valuable resource for patient manage- 30. Ambrosone CB, Ciupak GL, Bandera EV, et al. Conducting molecular
ment. Br J Haematol. 2001;113(1):3–10. epidemiological research in the age of HIPAA: a multi-institutional case-
9. Harris RL, Harrison CJ, Martineau M, et al. Is trisomy 5 a distinct cyto- control study of breast cancer in African-American and European-
genetic subgroup in acute lymphoblastic leukemia? Cancer Genet Cytogenet. American women. J Oncol. 2009;2009:871250.
2004;148(2):159–162. 31. Kuperwasser C, Chavarria T, Wu M, et al. Reconstruction of functionally
10. Harewood L, Robinson H, Harris R, et al. Amplification of AML1 on a normal and malignant human breast tissues in mice. Proc Natl Acad Sci
duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 U S A. 2004;101(14):4966–4971.
cases. Leukemia. 2003;17(3):547–553. 32. Proia DA, Kuperwasser C. Reconstruction of human mammary tissues in
11. Moorman AV, Richards SM, Robinson HM, et al. Prognosis of children a mouse model. Nat Protoc. 2006;1(1):206–214.
with acute lymphoblastic leukemia (ALL) and intrachromosomal amplifi- 33. Wu M, Jung L, Cooper AB, et al. Dissecting genetic requirements of
cation of chromosome 21 (iAMP21). Blood. 2007;109(6):2327–2330.
Downloaded from jnci.oxfordjournals.org at NIH Library on March 25, 2011
human breast tumorigenesis in a tissue transgenic model of human breast
12. Akasaka T, Balasas T, Russell LJ, et al. Five members of the CEBP cancer in mice. Proc Natl Acad Sci U S A. 2009;106(17):7022–7027.
transcription factor family are targeted by recurrent IGH translocations 34. Gupta PB, Proia D, Cingoz O, et al. Systemic stromal effects of estrogen
in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood. promote the growth of estrogen receptor-negative cancers. Cancer Res.
2007;109(8):3451–3461.
2007;67(5):2062–2071.
13. Russell LJ, Akasaka T, Majid A, et al. t(6;14)(p22;q32): a new recurrent
35. Bleyer A, Barr R, Hayes-Lattin B, et al. The distinctive biology of cancer
IGH@ translocation involving ID4 in B-cell precursor acute lympho-
in adolescents and young adults. Nat Rev Cancer. 2008;8(4):288–298.
blastic leukemia (BCP-ALL). Blood. 2008;111(1):387–391.
36. Hill DA, Furman WL, Billups CA, et al. Colorectal carcinoma in child-
14. Russell LJ, De Castro DG, Griffiths M, et al. A novel translocation,
hood and adolescence: a clinicopathologic review. J Clin Oncol. 2007;25(36):
t(14;19)(q32;p13), involving IGH@ and the cytokine receptor for erythro-
5808–5814.
poietin. Leukemia. 2009;23(3):614–617.
37. Liang JT, Huang KC, Cheng AL, et al. Clinicopathological and molecular
15. Russell LJ, Capasso M, Vater I, et al. Deregulated expression of cytokine
biological features of colorectal cancer in patients less than 40 years of age.
receptor gene, CRLF2, is involved in lymphoid transformation in B-cell
Br J Surg. 2003;90(2):205–214.
precursor acute lymphoblastic leukemia. Blood. 2009;114(13):2688–2698.
38. Liu B, Farrington SM, Petersen GM, et al. Genetic instability occurs in the
16. Stock W, La M, Sanford B, et al. What determines the outcomes for
majority of young patients with colorectal cancer. Nat Med. 1995;1(4):348–352.
adolescents and young adults with acute lymphoblastic leukemia treated
39. Kakar S, Aksoy S, Burgart LJ, et al. Mucinous carcinoma of the colon:
on cooperative group protocols? A comparison of Children’s Cancer
correlation of loss of mismatch repair enzymes with clinicopathologic
Group and Cancer and Leukemia Group B studies. Blood. 2008;112(5):
features and survival. Mod Pathol. 2004;17(6):696–700.
1646–1654.
40. Durno C, Aronson M, Bapat B, Cohen Z, Gallinger S. Family history and
17. Boissel N, Auclerc MF, Lheritier V, et al. Should adolescents with acute
molecular features of children, adolescents, and young adults with colo-
lymphoblastic leukemia be treated as old children or young adults?
rectal carcinoma. Gut. 2005;54(8):1146–1150.
Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol.
2003;21(5):774–780. 41. Sultan I, Rodriguez-Galindo C, El-Taani H, et al. Distinct features of
18. de Bont JM, Holt B, Dekker AW, van der Does-van den Berg A, colorectal cancer in children and adolescents: a population-based study of
Sonneveld P, Pieters R. Significant difference in outcome for adolescents 159 cases. Cancer. 2010;116(3):758–765.
with acute lymphoblastic leukemia treated on pediatric vs adult protocols 42. Lynch HT, Lynch JF, Lynch PM, Attard T. Hereditary colorectal cancer
in the Netherlands. Leukemia. 2004;18(12):2032–2035. syndromes: molecular genetics, genetic counseling, diagnosis and manage-
19. Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lym- ment. Fam Cancer. 2008;7(1):27–39.
phoblastic leukaemia: outcome on UK national paediatric (ALL97) and 43. Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have
adult (UKALLXII/E2993) trials. Pediatr Blood Cancer. 2007;48(3): we so far seen only the tip of an iceberg? Hum Genet. 2008;124(2):105–122.
254–261. 44. Engle SJ, Hoying JB, Boivin GP, et al. Transforming growth factor beta1
20. Barry E, DeAngelo DJ, Neuberg D, et al. Favorable outcome for adoles- suppresses nonmetastatic colon cancer at an early stage of tumorigenesis.
cents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Cancer Res. 1999;59(14):3379–3386.
Institute Acute Lymphoblastic Leukemia Consortium Protocols. J Clin 45. Simon R, Korn EL, McShane LM, Radmacher MD, Wright GW, Zhao
Oncol. 2007;25(7):813–819. Y. Design and Analysis of DNA. Microarray Investigations. New York, NY:
21. Benz CC. Impact of aging on the biology of breast cancer. Crit Rev Oncol Springer-Verlag; 2004.
Hematol. 2008;66(1):65–74. 46. Simon R. Interpretation of genomic data: questions and answers. Semin
22. Yau C, Fedele V, Roydasgupta R, et al. Aging impacts transcriptomes but Hematol. 2008;45(3):196–204.
not genomes of hormone-dependent breast cancers. Breast Cancer Res. 47. Rubinstein LV. Therapeutic studies. Hematol Oncol Clin North Am. 2000;
2007;9(5):R59. 14(4):849–876. ix.
23. Kerlikowske K, Molinaro A, Cha I, et al. Characteristics associated with 48. Green S, Benedetti J, Crowley J. Clinical Trials in Oncology. 2nd ed. Boca
recurrence among women with ductal carcinoma in situ treated by lump- Raton, FL: Chapman & Hall/CRC Press; 2003.
ectomy. J Natl Cancer Inst. 2003;95(22):1692–1702. 49. McShane LM, Hunsberger S, Adjei AA. Effective incorporation of bio-
24. Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast cancer markers into phase II trials. Clin Cancer Res. 2009;15(6):1898–1905.
before age 40 years. Semin Oncol. 2009;36(3):237–249. 50. Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized
25. Anders CK, Hsu DS, Broadwater G, et al. Young age at diagnosis corre- phase II trials and a proposal for phase II screening trials. J Clin Oncol.
lates with worse prognosis and defines a subset of breast cancers with 2005;23(28):7199–7206.
jnci.oxfordjournals.org JNCI | Commentary 7

8. 51. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR, eds. Introduction We acknowledge the fine work of Margaret Ames, Genevieve Medley,
to Meta-Analysis. West Sussex, UK: John Wiley & Sons; 2009. Denise Stredrick, and Susanne Strickland of the Office of Scientific Planning
and Assessment at the NCI.
Funding
Affiliations of authors: Division of Cancer Treatment and Diagnosis (JVT,
Lance Armstrong Foundation and National Cancer Institute.
NLS) and Division of Cancer Biology (DGB), National Cancer Institute,
Rockville, MD; Department of Pediatrics, Adolescent and Young Adult
Notes Oncology Program, University of North Texas Health Science Center and
The AYA Workshop co-chairs were B. Hayes-Lattin and K. Albritton . Cook Children’s Medical Center, Fort Worth, TX (KA); Department of
Breakout sessions were chaired as follows; ALL, N. L. Seibel; breast cancer, Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health
D. G. Blair; and colon cancer, J. V. Tricoli. and Science University, Portland, OR (BH-L).
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