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Aya jnci paper full april 20_2011

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    Aya jnci paper full april 20_2011 Aya jnci paper full april 20_2011 Document Transcript

    • JNCI JournalDOI: 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.COMMENTARYUnique Characteristics of Adolescent and Young Adult AcuteLymphoblastic Leukemia, Breast Cancer, and Colon CancerJames V. Tricoli, Nita L. Seibel, Donald G. Blair, Karen Albritton, Brandon Hayes-LattinManuscript 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, 6130Executive 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 hasbeen little improvement in survival of adolescent and young adult (AYA) cancer patients since 1975 when collected data Downloaded from jnci.oxfordjournals.org at NIH Library on March 25, 2011became adequate to evaluate this issue. In 2006, the AYA Oncology Progress Review Group made recommendations foraddressing the needs of this population that were later implemented by the LIVESTRONG Young Adult Alliance. One of theiroverriding questions was whether the cancers seen in AYA patients were biologically different than the same cancers in adultand/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 thesecancers and to discuss the next steps to improve their prognosis and treatment.J Natl Cancer Inst 2011;103:1–8One reason that there has been less progress in treating cancers among pediatric ALL patients vary depending on the presence ofamong adolescents and young adults might be that the biology is various recurring cytogenetic abnormalities. ALL patients withdifferent from the same diseases in younger and older individuals. “good” prognosis cytogenetics (such as trisomies of chromosomesThe Progress Review Group on adolescent and young adult (AYA) 4, 10, or 17, or t(12;21)/TEL-AML1) had relatively high survivaloncology 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 inleukemias, lymphomas, and breast and colorectal carcinomas” and the frequencies of various cytogenetic abnormalities among AYAinvestigate 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 commonfor a unique biology in these AYA cancers to distinguish them in AYA ALL (2). Under the auspices of the National Cancerfrom 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 Applicableunderstanding 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 withAYA Acute Lymphoblastic Leukemia “high-risk” ALL (mean age = 13.5 years, with white blood cellAcute lymphoblastic leukemia is one of the leading causes of can- counts higher than 50 000/mm3 at presentation) who had beencer-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 distinctyears 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 noveltherapy, 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 ofResearch and Treatment Center) discussed evidence that outcomes CRLF2, GPR110, MUC4, and other genes associated with activatedjnci.oxfordjournals.org JNCI | Commentary 1
    • Table 1. Special features of cancers in adolescent and young adult (AYA ) patientsFeatures 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 methylationFeatures 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 nodesFeatures 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 Downloaded from jnci.oxfordjournals.org at NIH Library on March 25, 2011tyrosine kinases, and frequent deletions of IKZF1, BTLA/CD300, 5 years, there was a 71% incidence of a recurrence in patientsRAG1-2, and EBF1. It was also associated with Hispanic or Latino harboring both lesions as compared with 18% incidence inrace (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 (Northernwere 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 treatmentspathways, along with IKZF1 deletion, cooperate to promote leuke- on 1205 AYA patients, aged 13–24 years (8). Nearly 500 of thesemogenesis. 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 AYAthat in preliminary studies, AYA ALL cancers appeared to be ge- patients of the same age had worse outcomes when treated on annetically similar to high-risk pediatric ALL. Working with the adult ALL protocol vs a pediatric ALL protocol. Of this group ofNCI 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. MostWillman 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 abnormalitiesof pediatric, adolescent, and young adult ALL. The genetic basis varied among children, AYAs, and adults. For example, theof treatment failure is particularly poorly understood in the AYA CALM-AF10 translocation occurred more frequently in AYAspopulation because it often occurs in patients lacking known high- than in children or adults. Of the 837 AYA patients in this grouprisk 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 withpresented the results of an integrated genomic analysis of B-cell pre- the same translocation (2%). Greater than 50% of AYA BCP-ALLcursor (BCP) samples that lacked known high-risk genetic alter- patients had a visible abnormality of chromosome arm 9p, whereasations from a cohort of high-risk pediatric and adolescent ALL other AYA BCP-ALL patients exhibited trisomies of chromosomespatients (COG P9906 cohort). They identified deletions and point 21, 8, or 5. Trisomy 5 as a sole cytogenetic change has previouslymutations 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 aboutratio = 2.40; 95% confidence interval = 1.38 to 4.2). The gene 3% in older children with ALL (median age 9 years) and accountsexpression signatures of these patients were very similar to those of for 5% of AYA (10); it is associated with BCP immunophenotypeBCR-ABL1 ALL patients, and by resequencing, activating muta- and low white blood cell count. Data from the Medical Researchtions of Janus kinases (JAK1, JAK2, and JAK3) were identified in Council ALL97 trial revealed that patients with iAMP21 had very11% 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 waswith very poor outcome when combined with IKZF1 deletions. 29%, whereas overall survival was 71%) following treatment forWhen analysis was restricted to the adolescent ALL cases (N = 58; their relapsed disease (11). Currently, these patients are being16–21 years of age), similar results were found: 50 of these patients treated as at high risk in the Medical Research Council ALL2003lacked a sentinel chromosomal alteration; however, they had a childhood ALL trial. Other translocations observed in BCP-ALLhigh frequency of JAK mutations and IKZF1 deletions, and in involve the immunoglobulin heavy chain locus (IGH@) and are2 Commentary | JNCI Vol. 103, Issue 8 | April 20, 2011
    • seen more frequently in older children and adolescents as com- Institute) described a pilot study that was initiated to determine thepared 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 50lenges 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 (agedcomes (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 retrospectivecomparison of 16–20 year olds with ALL who were treated on theChildren’s Cancer Group (CCG) or Cancer and Leukemia Group AYA Breast CancerB (CALGB) ALL protocols revealed that despite similar remission Breast cancer is the second most common cause of cancer-relatedrates between the two treatment groups, there was a statistically death for women in the United States and is the leading cause ofsignificantly lower 7-year EFS among those participants treated cancer death for young women aged 15–29 years. Younger womenon the CALGB protocol as well as a higher rate of central nervous with breast cancer exhibit an increased likelihood of recurrencesystem 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 Workshopthe pediatric protocols featured substantially more nonmyelosup- was to address the hypothesis that a unique biology may underliepressive therapy (vincristine, corticosteroids, and l-asparaginase) the distinctive properties of breast cancer in adolescent and young Downloaded from jnci.oxfordjournals.org at NIH Library on March 25, 2011elements 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) notedpatients in France, the United Kingdom, and the Netherlands; that the link between breast cancer and aging is poorly understoodnearly identical remission rates were observed, but EFS and sur- and that late-onset breast cancers are more likely to overexpressvival were substantially better for AYA patients enrolled on the estrogen receptor (ER)-a and progesterone receptor (PR), whereaspediatric trials (67% vs 41% 5-year EFS in France; 71% vs 56% breast cancers in women younger than 40 years are more likely5-year overall survival in the United Kingdom, and 71% vs 38% to be “triple-negative,” lacking overexpression of ER, PR, and5-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 associatedclinical, 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 ofences in protocol design and dose intensity, and potential varia- different ages with breast cancer, early-onset ER-positive breasttions 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 breastoncologists 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 agedprospective trial that focuses specifically on AYAs (Intergroup trial 70 years or older with those that were diagnosed in womenC10403). Newly diagnosed ALL patients between ages 16 and 40 younger than age 45 years revealed differences in gene expressionyears are eligible for treatment that parallels the current COG microarray profiles but no age-associated genomic differencesstudy 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 ofthat is essential for growth, is considered to be part of the standard early metastatic relapse regardless of age at diagnosis. Fortreatment in pediatric ALL protocols. However, because of tox- ER-negative breast cancer, better biomarkers are needed to predicticity and limited tolerability in older adults, medical oncologists do patient outcome and treatment responsiveness, and more studiesnot routinely use it. Since 1973, the Dana-Farber Cancer Institute are needed to evaluate the biological heterogeneity of early-onsetALL 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 specificas 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 tofor 20–30 weeks. Fifty-one patients aged 15–18 years were treated develop invasive cancer. Although DCIS is relatively rare in youngin two consecutive Dana-Farber Cancer Institute ALL Consortium women, the tendency to reoccur is higher in this population. Thetrials. Compared with patients aged 1–10 years, older adolescents UCSF DCIS Clinical Cohort Study identified biomarkers in theexperienced more thromboembolic complications (2% in 1–10 lesions of women with DCIS that can predict future diagnosis ofyear olds vs 14% in 10–15 year olds vs 10% in 15–18 year olds, invasive breast cancer (23), and a molecular signature in whichP < .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-regulatedthis favorable outcome, Dr Lewis Silverman (Dana-Farber Cancer proliferation markers (E2F and cyclin E1) and cyclooxygenase-2jnci.oxfordjournals.org JNCI | Commentary 3
    • collectively characterize the basal-like breast tumors that are more Dr Charlotte Kuperwasser (Tufts University School offrequently seen in younger women, and high cyclooxygenase-2 Medicine) described her human-in-mouse model in which humanand 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 thatspecific predictive tests for basal-like DCIS cancers to alleviate organize both structurally and functionally in mice (31,32) and arewomen’s anxiety regarding treatment and prognosis that accom- virtually indistinguishable from breast tissue taken directly frompanies 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 estrogenproperties of stem cells or premalignant cells and suggested that in breast cancer formation and progression. Estrogen acceleratedpremalignant 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 colonexplained 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 cellspremenopausal 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 estrogensintake of red meat, and high breast density) are not exclusive to apparently lacked the ability to respond directly to the hormone, Downloaded from jnci.oxfordjournals.org at NIH Library on March 25, 2011early-onset breast cancer. Early-onset tumors were associated with suggesting that estrogen may work indirectly to promote cancer infamily history of the disease, a more aggressive phenotype, younger women (34).ER- and/or PR-negative status, and compared with tumors in womenolder than age 30 years, were larger and more often associated withpositive 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 withclinicopathologic features, and oncogenic pathway deregulation in colorectal cancer have a poorer prognosis and more aggressivemore than 700 tumors according to patients’ ages. They confirmed disease than older adults (35). However, the biological basis anddifferences in pathology and mRNA expression of ER, PR, HER2, the clinical ramifications of this observation remain incompletelyand 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 adultsprognosis. Compared with tumors in older women, tumors from includes diagnosis at a more advanced tumor stage, greateryoung 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 inkinase 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 contrarybreast 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 levelsyounger 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 increasedegies 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 inreported 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 riskage 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 offirmed 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 tumorswhen younger women were compared. Also, regardless of race, exhibit chromosomal instability that is associated with eitherwomen younger than age 40 years were more likely than women inherited or somatic mutation of the APC gene. Chromosomeaged 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 colorectalare needed. cancer (HNPCC, also called Lynch syndrome) is an autosomal4 Commentary | JNCI Vol. 103, Issue 8 | April 20, 2011
    • dominant syndrome without polyposis that is associated with an features noted may contribute to a perceived poorer outcome inapproximately 70% lifetime risk of colorectal cancer (often right- children with colorectal cancer, the markedly higher incidence ofsided) and a 50%–70% risk of endometrial cancer (42). The auto- mucinous and signet ring adenocarcinoma in children suggestssomal dominant form is caused by heterozygous mutations in one that there are potentially important biological differences betweenof 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) andtheir 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 withColorectal tumors with MLH1 silencing or from patients with early-onset colorectal cancer are more likely than older patients toHNPCC 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 haveanalysis of MMR protein expression by immunohistochemistry. In a higher proportion of rectal cancers. For patients younger thanvery 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 thaninherits a mutation in the same MMR gene from both parents. The 45 years have worse outcomes than their older counterpartsclinical 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 Downloaded from jnci.oxfordjournals.org at NIH Library on March 25, 2011cinous and right-sided than in older populations, consistent with cancers that affect the very young. Such biological differences maythe increased prevalence of HNPCC-associated tumors in this be associated with inherited predisposing syndromes or with otherpopulation. Between 80% and 90% of tumors from patients with risk factors, such as inflammatory bowel disease, whose incidenceHNPCC 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 Cancerwithin the TGFBR2 gene. Up to 30% of all human colorectal can- Center) pointed out that there are few reports of colorectal cancercers have mutations in transforming growth factor- (TGF)-b sig- in patients aged 30 years and younger, and most that do exist arenaling–related genes. Dr Thomas Doetschman (BIO5 Institute) case histories or small institutional series. To address this deficit, adiscussed a TGFb1-deficient mouse model that displayed features retrospective multi-institutional review was conducted using aof human colorectal cancer in that the colon cancer was associated total of 167 patients aged 10–30 years (median age = 21 years) whowith inflammatory lesions, occurred in the cecum and proximal were identified through a survey of COG institutions; of thesecolon, 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 weremucinous 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 wasregarding disease mechanisms in colorectal cancer that will con- observed in 23% of the tumors and was more commonly seen intribute 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 48from the Surveillance, Epidemiology, and End Results program months follow-up, median overall survival for this cohort was 44that suggested that colorectal cancer has a similar natural history months: 88 of 159 patients died. Compared with adult patients, ain patients aged 15–29 years and in older patients. It has been higher proportion of AYA colorectal cancer patients had stage IIIspeculated that delayed diagnosis and treatment play a role in the and IV disease and a worse overall prognosis. The proportion ofpoorer outcomes observed among AYAs. A retrospective review of tumors with signet ring cell characteristics was also higher but was77 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 outcomesdren (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 stablethan 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 amongfound in adults and include abdominal pain, weight loss, and patients of this age group was associated with unique clinical andanemia, but the rarity of colorectal cancer in children compared biological properties.with other causes of abdominal discomfort often prolongs theinterval from onset of symptoms to diagnosis. In this study, thelength of this interval did not appear to be associated with outcome Statistical Issues in Working With the AYAbecause children who presented with an acute onset of symptoms Populationinvariably 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 cancersjnci.oxfordjournals.org JNCI | Commentary 5
    • and clinical trial design. Key issues include whether AYA cancers differences and their impact on therapy and on protocol adherenceare biologically homogeneous or reflect heterogeneous subtypes, by both physicians and patients. It is crucial to let AYA patients andand whether they are distinct from pediatric and adult cancers or referring physicians know the importance of treatment at cancer ormerely reflect a shift in subtype distribution. Clinically, it will be academic centers that understand the value of sometimes treatingimportant to identify prognostic and predictive biological subtypes AYA patients using pediatric rather than adult protocols and canthat relate to disease natural history or predict patient response to provide access to clinical trials. Currently, there are no knowncertain 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 biologicallyapproach to elucidate the biology of AYA cancers and develop in- unique; however, there may be an enrichment of certain breastformative clinical tools. Unsupervised statistical analysis methods cancer subtypes among this age group and further research issuch 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 consensusmethods are available to construct prognostic or predictive classi- that these tumors should be categorized as high risk based solelyfiers 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. Downloaded from jnci.oxfordjournals.org at NIH Library on March 25, 2011lenging. Phase I trials of AYA cancers should include The evidence that AYA colorectal cancers may differ biologicallypharmacokinetic 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 chromosomeuling. Single-arm phase II trials may require less than half the stability, and increased rate of MMR-D in AYA colorectal cancersample size of some randomized phase II trials to achieve compa- patients. Some of this evidence is anecdotal, and the perception thatrable type I (a) and type II (b) error. However, their reliance on survival rates for AYA patients with colon cancer are lower thanhistorical benchmarks can be problematic, particularly if AYA those observed in older patients is not supported by existingcancers represent rare biological subtypes (49). Various random- Surveillance, Epidemiology, and End Results data. However, thereized phase II trial designs have been proposed for rare cancers: for may be substantial differences in biology and other features betweenexample, when screening trials are done for preliminary compar- different age groups even within the population of AYA patientsison of an experimental treatment to the standard regimen, the with colorectal cancer. If age is a good surrogate for a unique tumorscreening design allows for larger type I and II errors and targets a biology associated with AYA cancers, then studies of colorectallarger effect size than a phase III trial (50), thereby allowing cancer in AYA patients will almost certainly illuminate alternativesmaller 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, sittinglikely 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 stepsassay 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 featuresfrom the experimental therapy. Factorial designs can test multiple of these cancers that distinguish them from the adult and pediatrictreatments in combination so that patients serve “double duty” to versions and 2) to elucidate whether these differences can in someprovide information on more than one treatment, but interpreta- way explain their clinical behavior. Only in this way will we able totion can be complicated if treatment interaction effects are present. develop new approaches for identifying targets for AYA cancerSystematic 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 fruitfulif 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-riskwhether there are biological differences based on age. For ALL, childhood acute lymphoblastic leukemia. 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    • 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 AdultNotes Oncology Program, University of North Texas Health Science Center andThe AYA Workshop co-chairs were B. Hayes-Lattin and K. Albritton . Cook Children’s Medical Center, Fort Worth, TX (KA); Department ofBreakout sessions were chaired as follows; ALL, N. L. Seibel; breast cancer, Hematology and Medical Oncology, Knight Cancer Institute, Oregon HealthD. G. Blair; and colon cancer, J. V. Tricoli. and Science University, Portland, OR (BH-L). Downloaded from jnci.oxfordjournals.org at NIH Library on March 25, 20118 Commentary | JNCI Vol. 103, Issue 8 | April 20, 2011