Correspondence

Puberty and Genetic Susceptibility to Breast Cancer

N Engl J Med 2003; 349:1088-1089September 11, 2003

Article

To the Editor:

Hamilton and Mack (June 5 issue)1 note that in twins with the greatest genetic susceptibility to breast cancer, the strongest influence on age at diagnosis was “earlier puberty.” They used the age at which the breasts developed as an indicator of the onset of puberty. We recently reported a study of 443 girls followed from the ages of 9 and 10 years who had either breast development or pubic-hair development, but not both, at the onset of puberty.2 The age at the onset of puberty was similar in the two groups of girls. Those who had breast development first had an earlier age at menarche and had a greater body-mass index and adiposity throughout puberty and into early adulthood. These factors are associated with breast cancer.3,4

Hamilton and Mack, when reporting on the initiation of puberty according to the age at the time of breast development, may have unintentionally oversampled girls whose breasts first developed by not including pubic-hair development in their analysis. The findings of these two studies1,2 still cannot establish whether the hormonal milieu or the cellular response to the pubertal milieu is the more important factor, but they may help direct studies of gene-hormone-receptor interactions among young girls.

Frank M. Biro, M.D.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229

4 References

1. 1

   Hamilton AS, Mack TM. Puberty and genetic susceptibility to breast cancer in a case-control study in twins. N Engl J Med 2003;348:2313-2322
   Full Text | Web of Science | Medline

2. 2

   Biro FM, Lucky AW, Simbartl LA, et al. Pubertal maturation in girls and the relationship to anthropometric changes: pathways through puberty. J Pediatr 2003;142:643-646
   CrossRef | Web of Science | Medline

3. 3

   Garland M, Hunter DJ, Colditz GA, et al. Menstrual cycle characteristics and history of ovulatory infertility in relation to breast cancer risk in a large cohort of US women. Am J Epidemiol 1998;147:636-643
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   Rockhill B, Moorman PG, Newman B. Age of menarche, time to regular cycling, and breast cancer (North Carolina, United States). Cancer Causes Control 1998;9:447-453
   CrossRef | Web of Science | Medline

To the Editor:

Hamilton and Mack suggest that breast carcinoma in twins shows that the hereditary and sporadic forms of the disease have different pathogenic mechanisms. Indeed, two types of breast carcinoma have long been suspected1: one has an early onset and is hormone-dependent and the other has a late onset and is hormone-independent. My colleagues and I have conceptualized these early-onset and late-onset juxtaposed types of breast carcinoma as probabilistic (bell-shaped) curves (Figure 1Figure 1Conceptualized Bimodal Frequency Distribution of Early-Onset and Late-Onset Breast Carcinoma, According to Age at Diagnosis.).2

Hamilton and Mack may have identified these same two types in their twin cohort. The cancer in disease-concordant monozygotic pairs, representing hereditary breast carcinoma, appeared to be linked to hormonal exposures early in reproductive life, as we concluded for estrogen-receptor–negative tumors and inflammatory and medullary breast carcinomas in the general population.2-4 In contrast, the cancer in disease-discordant twins, which represented sporadic breast carcinoma, seemed to be dependent on cumulative lifetime exposures, as we noted for estrogen-receptor–positive tumors and ductal, lobular, tubular, papillary, and mucinous breast carcinomas. Hamilton and Mack's case–control study in twins supports the hypothesis that age-specific hormonal exposures affect some breast carcinomas more than others, a conclusion that is consistent with population-based observations.

William F. Anderson, M.D.
National Cancer Institute, Bethesda, MD 20892
wanderso@mail.nih.gov

4 References

1. 1

   Moolgavkar SH, Lee JA, Hade RD. Comparison of age-specific mortality from breast cancer in males in the United States and Japan. J Natl Cancer Inst 1978;60:1223-1225
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2. 2

   Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat 2002;76:27-36
   CrossRef | Web of Science | Medline

3. 3

   Anderson WF, Chu KC, Sherman ME, Chang S. Distinct morphologic patterns for age-specific breast carcinoma incidence rates in the Surveillance, Epidemiology, and End Results database. Prog Proc Am Soc Clin Oncol 2003;22:846-846 abstract.
   

4. 4

   Anderson WF, Chu KC, Chang S. Inflammatory breast carcinoma and noninflammatory locally advanced breast carcinoma: distinct clinicopathologic entities? J Clin Oncol 2003;21:2254-2259
   CrossRef | Web of Science | Medline

Author/Editor Response

Biro and colleagues1 have reported that the sequence of pubertal events may differ among girls, with the development of either breasts (“thelarche”) or pubic hair (“adrenarche”) occurring first. In his letter, Biro suggests that our finding of genetic susceptibility to pubertal events2 may pertain only to the former. Because our subjects were ascertained by means of the appearance of breast cancer, we presume that both sequences were represented. Even among those in the adrenarche pathway, a difference between the twins within a pair in the appearance of breasts and menarche would be expected. Since identical twins are likely to be matched according to pathway, comparisons between the two twins within a pair would be matched according to the sequence of events. Thus, we have no reason to presume that our finding was restricted to the thelarche subgroup. Because our twins did not have any abnormalities with respect to puberty, including age at onset, our study supports the hypothesis that it is the cellular response to the onset of hormones at puberty that is the factor most likely to be related to the increased risk. We agree that studies of gene–hormone–receptor interactions in young girls are important.

Anderson suggests that we identified two previously identified subtypes of breast cancer, with the hereditary breast cancers representing early-onset, estrogen-receptor–negative tumors and the sporadic tumors representing later-onset, estrogen-receptor–positive tumors. (We think he meant to say that the former were hormonally independent tumors, whereas the latter were hormonally dependent tumors.) Other information that we have on these cases does not support this conclusion. We have previously reported that the hereditary tumors in these twins were likely to be positive for estrogen receptors,3 and in 45 percent of the monozygotic pairs in which both twins had breast cancer, the first case occurred at the age of 50 years or older. This difference between our findings and previous assumptions regarding the characteristics of hereditary breast cancer is an important one. Our evidence suggests that both “sporadic” and hereditary breast cancer are hormonally dependent in different ways and that hereditary breast cancer, triggered early by the events of puberty, can occur either before or after menopause.

Ann S. Hamilton, Ph.D.
Thomas M. Mack, M.D.
University of Southern California, Los Angeles, CA 90089-9175
ahamilt@usc.edu

3 References

1. 1

   Biro FM, Lucky AW, Simbartl LA, et al. Pubertal maturation in girls and the relationship to anthropometric changes: pathways through puberty. J Pediatr 2003;142:643-646
   CrossRef | Web of Science | Medline

2. 2

   Hamilton AS, Mack TM. Puberty and genetic susceptibility to breast cancer in a case-control study in twins. N Engl J Med 2003;348:2313-2322
   Full Text | Web of Science | Medline

3. 3

   Mack TM, Hamilton AS, Press MF, Diep A, Rappaport EB. Heritable breast cancer in twins. Br J Cancer 2002;87:294-300
   CrossRef | Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   Susan Olivo-Marston, Barry I. Graubard, Kala Visvanathan, Michele R. Forman. (2010) Gender-specific differences in birthweight and the odds of puberty: NHANES III, 1988-94. Paediatric and Perinatal Epidemiology 24:3, 222-231
   CrossRef

2. 2

   W. F. Anderson, R. Matsuno. (2006) Breast Cancer Heterogeneity: A Mixture of At Least Two Main Types?. JNCI Journal of the National Cancer Institute 98:14, 948-951
   CrossRef

3. 3

   William F. Anderson, Ismail Jatoi, Susan S. Devesa. (2005) Distinct breast cancer incidence and prognostic patterns in the NCI?s SEER program: suggesting a possible link between etiology and outcome. Breast Cancer Research and Treatment 90:2, 127-137
   CrossRef