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Breast Cancer after Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Lisa B. Kenney, MD; Yutaka Yasui, PhD; Peter D. Inskip, ScD; Sue Hammond, MD; Joseph P. Neglia, MD; Ann C. Mertens, PhD; Anna T. Meadows, MD; Debra Friedman, MD; Leslie L. Robison, PhD; and Lisa Diller, MD
[+] Article and Author Information

From Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Cancer Prevention Program, Fred Hutchinson Cancer Research Center, and University of Washington School of Medicine, Seattle, Washington; National Cancer Institute, Bethesda, Maryland; Children's Hospital and Ohio State University College of Medicine and Public Health, Columbus, Ohio; University of Minnesota School of Medicine, Minneapolis, Minnesota; and The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.


Acknowledgment: The authors thank Yan Liu for her expert assistance in data analysis.

Grant Support: By the National Cancer Institute, Bethesda, Maryland (grant CA 55727); Children's Cancer Research Fund, Minneapolis, Minnesota; David B. Perini, Jr. Quality of Life Clinic, Boston, Massachusetts; and Swim-Across-America Foundation.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Lisa B. Kenney, MD, David B. Perini, Jr. Quality of Life Clinic, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; e-mail, Lisa_Kenney@DFCI.harvard.edu.

Current Author Addresses: Drs. Kenney and Diller: David B. Perini, Jr. Quality of Life Clinic, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.

Dr. Yasui: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, PO Box 19024, 1100 Fairview Avenue North, M4-B402, Seattle, WA 98109-1024.

Mr. Inskip: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Executive Plaza South, Room 7052, Bethesda, MD 20892.

Dr. Hammond: Anatomic Pathology, Children's Hospital, 700 Children's Drive, Columbus, OH 43205.

Dr. Neglia: Division of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, University of Minnesota, MMC 484, 420 Delaware Street SE, Minneapolis, MN 55455.

Dr. Mertens: Department of Pediatrics, University of Minnesota, MMC 715, 420 Delaware Street SE, Minneapolis, MN 55455.

Dr. Meadows: The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104.

Dr. Friedman: Children's Hospital and Regional Medical Center, Division of Hematology/Oncology, Mailstop 6D1, 4800 Sand Point Way NE, Seattle WA 98105.

Dr. Robison: Cancer Center, University of Minnesota, MMC 422, Minneapolis, MN 55455.

Author Contributions: Conception and design: L.B. Kenney, J.P. Neglia, D. Friedman, L.L. Robison, L. Diller.

Analysis and interpretation of the data: L.B. Kenney, Y. Yasui, P.D. Inskip, S. Hammond, J.P. Neglia, A.C. Mertens, D. Friedman, L.L. Robison, L. Diller.

Drafting of the article: L.B. Kenney, Y. Yasui.

Critical revision of the article for important intellectual content: L.B. Kenney, P.D. Inskip, J.P. Neglia, A.C. Mertens, A.T. Meadows, D. Friedman, L.L. Robison, L. Diller.

Final approval of the article: L.B. Kenney, P.D. Inskip, S. Hammond, J.P. Neglia, A.C. Mertens, A.T. Meadows, D. Friedman, L.L. Robison, L. Diller.

Provision of study materials or patients: S. Hammond, A.C. Mertens, D. Friedman, L.L. Robison.

Statistical expertise: Y. Yasui, P.D. Inskip.

Obtaining of funding: J.P. Neglia, A.C. Mertens, L.L. Robison.

Administrative, technical, or logistic support: S. Hammond, A.C. Mertens, L.L. Robison.

Collection and assembly of data: S. Hammond, L.L. Robison.


Ann Intern Med. 2004;141(8):590-597. doi:10.7326/0003-4819-141-8-200410190-00006
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We found that young female survivors of childhood sarcomas and those treated with chest radiation are at an increased risk for breast cancer compared with women in the age-matched general population. Breast cancer risk is increased by a family history of breast cancer or sarcoma, and history of pelvic radiation is protective. Thyroid disease is an indicator of increased risk in these young women, and unlike in the general population, menstrual and reproductive histories did not statistically significantly modify risk. Unexpectedly, almost one quarter of the breast cancer cases were diagnosed in women who had not been exposed to previous chest radiation. Thus, Hodgkin disease survivors treated with chest radiation therapy are not the only childhood cancer survivors who should be considered at risk for secondary breast cancer.

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Figure.
Cumulative incidence of breast cancer in survivors of Hodgkin disease, bone sarcoma and soft-tissue sarcoma, and other cancer diagnosis as a function of attained age in women exposed and not exposed to chest radiation therapy.
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This may be due to low DHEA...
Posted on October 19, 2004
James M. Howard
independent
Conflict of Interest: None Declared

The findings of Kenney, et al., may be explained. It is my hypothesis that low DHEA may trigger breast cancer and this is often accompanied and caused by high testosterone (1994). My hypothesis has received demonstrable support.

Hormone replacement therapy (HRT) increases the probability of breast cancer. I suggest this occurs because HRT and "estrogen replacement therapy" both reduce DHEA (Metabolism. 2001 Apr;50(4):488-93). Also, ""¦androstenedione and testosterone might be more strongly associated with [breast cancer] risk than estradiol." (J Natl Cancer Inst 2002; 94: 606- 616). Testosterone reduces DHEA.

Stahlberg, et al., reported: "In current users of combined HRT with testosterone-like progestins, the continuous combined regimens were associated with a statistically significant higher risk of breast cancer than the cyclical combined regimens"¦" (Int J Cancer. 2004 May 1;109(5):721-7) I suggest the reason for the increased risk caused by the "testosterone- like progestins" may be due to the possibility that they act like testosterone and reduce overall DHEA.

It is also my hypothesis that the "secular trend," the increase in size and earlier puberty occurring in our children actually is an increase in the percentage of individuals of higher testosterone within our populations. The secular trend is real and robust in the United States (Arch Pediatr Adolesc Med. 2000;154:155-161). More specifically, it is the exposure of fetuses to higher levels of testosterone in utero that is causing the secular trend, including the increase in breast cancer.

Kenney, et al., report risk factors for "breast cancer among female survivors of childhood cancer" that may also support my hypothesis. Total body irradiation of girls significantly reduced DHEA levels up to five years following treatment (Horm Res 1995; 43: 279-85). Conversely, in rats "DHEA has a potent preventive activity against the promotion/progression phase of radiation-induced tumorigenesis." (J Steroid Biochem Mol Biol 1995; 54: 47-53). Thyroid disease, hypo- and hyperthyroid conditions, exhibit decreases and increases in DHEA respectively. Pelvic radiation therapy frequently results in ovarian failure (AJR Am J Roentgenol 1989; 153: 1003-6). This may reduce the production of testosterone in this cohort and, therefore, reduce the effects of testosterone in reducing DHEA. The protective effect of pelvic radiation reported by Kenney, et al., may be due to reduced testosterone.

I suggest the findings of Kenney, et al., may represent various phenomena in their cohort which reduce DHEA and, therefore, increase breast cancer with the exception of pelvic radiation which may reduce the negative effect of testosterone , therefore, increasing DHEA.

Conflict of Interest:

None declared

High birth weight and secondary breast cancer
Posted on October 29, 2004
Gabriele Rossi
University of Pavia
Conflict of Interest: None Declared

I read with great interest the original article by Kenney and Collegues regarding the risk factors associated with the development of a secondary breast cancer in a childhood cancer survivors population(1). I would like to ask the Authors if they are able to perform their analysis taking into account the patients' birth weight. Recently, Ahlgren and Colleagues has emphasized the, already recognized, role of high birth weight as an independent risk factor for breast cancer(2). Moreover, it is known that there is a substantial literature indicating a positive association between high birth weight and the risk of developing some types of cancers (i.e. Wilms tumors, brain tumors, leukemia and lymphoma)(3-5). Theoretically therefore, in the contest of this particular studied population (in which patients suffer from a breast cancer after a childhood cancer), it should be not surprising to argue that high birth weight could somehow influence, in a same patient, the genesis of both tumors. It should be interesting to understand whether high birth weight may be considered as an independent risk factor for secondary breast cancer. In positive case, Clinicians would have a novel element to identify specific subgroup of childhood cancer survivors who, in turn, might benefit from early, vigilant screening for breast cancer.

1)Kenney LB, Yasui Y, Inskip PD, Hammond S, Neglia JP, Mertens AC, et al. Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med. 2004;141:590-7.

2)Ahlgren M, Melbye M, Wohlfahrt J, Sorensen TI. Growth patterns and the risk of breast cancer in women. New Engl J Med. 2004;351:1619-26.

3)Schuz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. High-birth weight and other risk factors for Wilms tumour: result of a population- based case-control study. Eur J Pediatr. 2001;160:333-8.

4)Hjalgrim LL, Rostgaard K, Hjalgrim H, Westergaard T, Thomassen H, Forestier E, et al. Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway and Iceland. J Natl Cancer Inst. 2004;96:1549-56.

5)Isager H, Andersen E. Pre-morbid factors in Hodgkin's disease. Birth weight and growth pattern from 8 to 14 years of age. Scand J Haematol. 1978;21:250-5.

Conflict of Interest:

None declared

In Response
Posted on January 18, 2005
Lisa B Kenney
Dana-Farber Cancer Institute
Conflict of Interest: None Declared

In response to Drs. Rossi and Howard, one of the objectives of our study was to investigate how hormonal and reproductive factors, known to modify breast cancer risk in the general population, modify secondary breast cancer risk in the unique population of childhood cancer survivors. The authors acknowledge that breast carcinogenesis is complex and ovarian steroid hormones are not the only factors that contribute to an individual's breast cancer risk. However, in our attempt to identify risk factors for secondary breast cancer beyond radiation treatment, we chose to focus on hormonal and reproductive factors that are well established as breast cancer risk factors for the general population (1). In addition, our analysis was limited to data that were available on this cohort. Future studies on secondary breast cancer risk in childhood cancer survivors might address potential risk factors that the readers put forth.

Lisa B. Kenney, MD, MPH Dana-Farber Cancer Institute Boston, MA 02115 Lisa_Kenney@DFCI.harvard.edu

1. Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl cancer Inst 1989; 81 (24): 1879-86.

Conflict of Interest:

None declared

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Summary for Patients

Breast Cancer in Women Who Survived Childhood Cancer

The summary below is from the full report titled “Breast Cancer after Childhood Cancer: A Report from the Childhood Cancer Survivor Study.” It is in the 19 October 2004 issue of Annals of Internal Medicine (volume 141, pages 590-597). The authors are L.B. Kenney, Y. Yasui, P.D. Inskip, S. Hammond, J.P. Neglia, A.C. Mertens, A.T. Meadows, D. Friedman, L.L. Robison, and L. Diller.

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