Cancer in Relatives of Survivors of Childhood Sarcoma Eileen Burke, RN,**T Frederick P. Li, MD,*$ Abbe J. Janov, MPH,* Stephen Batter, BA,* Holcombe Grier, MD,§ and Allen Goorin, MDS

Relatives of 88 long-term survivors of childhood sarcoma were examined for the familial cancer syndrome of sarcoma, breast cancer, and other neoplasms (Li- Fraumeni syndrome). Twenty-six of 402 close relatives developed cancer (expected, 23.8), including breast cancer in four mothers (expected, 3.1). Two sarcoma probands who developed second malignant tumors have multiple relatives with cancer and might have an inherited predisposition. An increased cancer risk and exceptional requirement for disease screening appear to be confined to first-degree relatives of a small fraction of children with sarcoma, notably probands with second cancers. Cancer 67:1467-1469,1991.

FAMILIAL CANCER SYNDROME has been described A of breast cancers in young mothers of children with sarcomas and other neoplasms (Li-Fraumeni ~yndrome). '-~ These reports raise the prospect that mothers of all children with sarcoma should be targeted for breast cancer screening in early a d ~ l t h o o d . ~ To eval- uate the proposed intervention, we conducted a retro- spective study of cancer occurrence among family mem- bers of our series of childhood sarcoma survivors.

Materials and Methods

A registry was established of long-term survivors of childhood cancer treated at the Dana-Farber Cancer In- ~ t i t u t e . ~ From the registry, 104 living patients were iden- tified who had a soft tissue sarcoma or osteosarcoma di- agnosed before 18 years of age from 1948 to 1976. These probands were requested to complete a mailed question- naire to update their personal medical record and family history of cancer in first-degree relatives (mother, father, and siblings). Excluded from study were survivors of Ew- ing's sarcoma, which is not a component of the familial cancer syndrome.'

From the *Clinical Studies Section, Clinical Epidemiology Branch, National Cancer Institute, Bethesda, Maryland; and the Divisions of SBiostatistics and Epidemiology and §Pediatric Oncology, Dana-Farber Cancer Institute and The Children's Hospital, Harvard Medical School, Boston, Massachusetts.

tRecipient of the Amy Potter Nursing Fellowship. Address for reprints: Frederick P. Li, MD, 44 Binney Street, M3A28,

Accepted for publication August 17, 1990. Boston, MA 02 1 15.

Eighty-eight probands, 35 women and 53 men, re- sponded to the survey. Sixty-one patients had a soft tissue sarcoma, and 27 had an osteosarcoma diagnosed before age 18 years. The respondents were 19 to 52 years of age (median, 30 years) and survived a sarcoma for 14 to 40 years (median, 22 years). Among the 16 nonresponders (1 5% of eligible cases), nine patients had been lost to fol- low-up for a median of 12 years; the other seven did not return the questionnaire.

The numbers of cancers reported in mothers, fathers, and siblings were compared with expected figures based on sex- and age-specific cancer incidence rates of the Sur- veillance, Epidemiology, and End Results Program, 1973- 1977.6 Medical and pathology records and death certifi- cates were sought to confirm reports of cancer in 26 rel- atives and were obtained for 21 of them. The diagnosis of cancer was based on pathology reports for 17 patients, death certificates for three, and clinical records for one. No false-positive report of cancer was found, prompting inclusion of the remaining five relatives in the analysis. Excluded from the analysis were benign neoplasms, in situ cancers, and carcinomas of the skin. Relative risk (RR) was used to compare observed and expected num- bers. Tests of statistical significance and confidence in- tervals (CI) were determined at the 0.05 level, assuming a Poisson distribution.' Subgroup analysis was done in the probands with second cancers; other studies indicate that relatives of such probands are prone to cancer.','

Results The 26 cancers among the 402 close relatives of sarcoma

probands approximate the 23.8 cancers expected (Table

1467

1468 CANCER March I 199 1 Vol. 67

1). There was no significant excess of cancers among the mothers, fathers, or siblings. Four of the mothers had breast cancer (expected, 3.1; RR, 1.3; CI, 0.4-3.3). Three breast cancers occurred before age 50 years (expected, 1.5) and the fourth thereafter (expected, 1.6). Cancers of other tissues and sites occurred in ten mothers, ten fathers, and two siblings. Component tumors of the Li-Fraumeni syn- drome, other than breast cancer, occurred in three adult family members (brain tumors at ages 39 and 62 years and acute leukemia at 45 years).' Sarcoma and adreno- cortical carcinoma, the remaining components of the syndrome, have not developed in these relatives.

Two of the 88 probands developed second cancers in previously irradiated sites: patient 1 had breast cancer after an osteosarcoma, and patient 2 had a schwannoma after rhabdomyosarcoma (Table 2).* The mother of patient 1 developed a lymphoma, an uncle reportedly had both melanoma and lymphoma, and a young cousin had breast cancer. A sister of patient 2 had an ovarian Sertoli-Leydig cell tumor, and a cousin reportedly had lung cancer. These families have some features of the Li-Fraumeni syndrome (breast cancer and sarcoma at early ages and multiple primary neoplasms), but a chance association cannot be excluded.' No family in the series showed evidence of other inherited predisposing disorders, such as neurofi- bromatosis type 1 .*

Discussion

In 1969, the Li-Fraumeni syndrome was described in four families with soft tissue sarcoma in children asso- ciated with breast cancers and other neoplasms in young relatives.' Follow-up of these families showed an excess occurrence of cancers in an autosomal dominant pat- tern." More than 50 affected kindreds have now been

identified and four additional components of the syn- drome recognized: osteosarcoma, acute leukemia, brain tumors, and adrenocortical carcinoma in childhood.' In addition, Strong el aL2 reported that first-degree relatives of 159 three-year survivors of childhood sarcoma had an increased frequency of cancers, particularly breast cancer, sarcoma, and other neoplasms occurring before 35 years of age. The excess cancers clustered in family members of probands with second malignant neoplasms, as noted in two of our patients. Birch et a/.' described eight breast cancers (expected, 3.3) in mothers of a population-based series of 177 children with soft tissue sarcoma in Man- Chester, England. Using the same registry, Hartley d L I ~ . ~

identified six breast cancers (expected, 2.1) among mothers of 86 children with osteosarcoma or chondrosarcoma. The breast cancers tended to occur before menopause in most of the Manchester mothers, including several with striking family histories of cancer.

Our study showed no overall excess of cancers among the first-degree relatives of 88 long-term survivors of childhood sarcoma. For breast cancer in mothers of sar- coma probands, the relative risk was lower in our series than in other published However, the differ- ences were small and based on few affected women in each series. Unlike prior studies, our probands were long- term survivors of sarcoma (median age, 30 years). Most of their mothers were postmenopausal, whereas breast cancer in families tends to occur at early When only premenopausal breast cancers were considered, the data for our series (relative risk, 2) were consistent with those for other ~ t u d i e s . ~ - ~ In our study design, decedents in the registry were excluded to reduce the number of nonresponders who might introduce selection bias. The decision systematically eliminated four sarcoma cases who died of a second cancer. A review of their records revealed

TABLE 1. Observed and Expected Numbers of Cancers in First-Degree Relatives of Survivors of Childhood Sarcoma

No. of first-degree relatives with cancer

Probands with sarcoma Probands with doublc First-degree only primary cancers All probands

relatives (no.) OBS (EXPI OBS (EXP) OBS (EXP)S

Mothers (88) All cancers 13 (9.3)

Other? 9 (6.3) Fatherst (88) 10 (10.8)

Siblings? (226) 1 (3.2)

Total (402) 24 (23.3)

Breast* 4 (3.0) I (0.3) 14 (9.6)

(0.1) 4 (3.1) 1 (0.2) 10 (6 .5) - (0.2) 10 (11.0)

2 (3.2) 1

2 (0.5) 26 (23.8)

-

-

* Four mothers had unilateral breast cancer at ages 37, 42, 49, and 82 years.

$ Cancers other than breast carcinoma: lymphoma ( 5 cases), lung (3), leukemia ( I ), brain tumor (2), and multiple myeloma, carcinoma of the

kidney, pancreas, tongue, bile duct, female reproductive system, prostate, colon, and esophagus (1 each).

3 No OBS/EXP ratio statistically significant at P = 0.05. See Methods for determination of OBS/EXP ratio.

No. 5 CANCER IN RELATIVES OF CHILDHOOD SARCO%A SURVIVORS - Burke et a/. 1469

TABLE 2. Cancers in Close Relatives of Probands With Multiple Primary Tumors

Tumor type (age at diagnosis in years) Patient

no. Proband Affected relatives*

1 Osteosarcoma (9) and breast Lymphoma in the carcinoma (38) mother (68)

2 Rhabdomyosarcoma (14) and Sertoli-Leydig cell tumor schwannoma (28) in a sister ( 14)

* Patient I also had an uncle with both melanoma and lymphoma at age 55 years and a female cousin with breast cancer at age 35 years, and Patient 2 had a cousin with lung cancer.

that multiple relatives of one patient had developed com- ponent tumors of the Li-Fraumeni syndrome;' the father of another had esophageal cancer. Addition of these pa- tients to the series would not alter our conclusion that the Li-Fraumeni syndrome is common only in children with sarcoma who also develop a second cancer.'

Studies to date have found breast cancer in less than 10% of mothers of sarcoma probands. Breast cancer in- cidence increases with age, and the premenopausal rate among these women approximates the postmenopausal rate among women in general.6 However, early detection by mammography may be less effective in younger women, including mothers of our probands." Further study is needed of the merits of targeting these mothers for breast cancer screening in early adulthood. Much less effort is required to obtain and periodically update a de- tailed family history of every child with sarcoma. The

data will identify the rare affected families for early disease detection and laboratory studies of mechanisms of car- cinogenesis in the Li-Fraumeni syndrome. l 2

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