23 October, 2012:

An article by Nichols and colleagues [1] provides a detailed analysis of data collected from 10,449 women with invasive breast cancer compared to 11,787 age-matched controls without breast cancer to determine whether the use of estrogen therapy following a bilateral oophorectomy prior to reaching a natural menopause had any influence on the development of breast cancer. In pooled data from the Collaborative Breast Cancer Studies population-based, case–control studies collected between 1992 and 2007, the use of estrogen prescribed for women, following total abdominal hysterectomy with bilateral salpingo-oophorectomy, was analyzed for subsequent development of breast cancer. Case participants were compared with age-matched control cohorts obtained by identifying women in a register of licensed drivers or from a list of Medicare beneficiaries.

A very confusing picture emerges from the results.

1. All women who had their ovaries removed before the age of 40 years were found to have a decreased risk of developing breast cancer – a 24% reduction following estrogen use and 30% reduction when no hormone was used.

2. Women over the age of 45 years when their ovaries were removed were found to have no reduction in the risk of breast cancer if they used estrogen therapy (but no increased risk).

3. Those women who began estrogen therapy within 5 years of bilateral oophorectomy had a 22% increased risk of breast cancer, whereas those who delayed estrogen use for 5 or more years had a 54% reduction in the risk of breast cancer.

4. Among current estrogen users, those women taking the hormone for less than 10 years had a 32% increased risk of breast cancer, whereas those using estrogen for longer than 10 years had no significant increase in breast cancer.

5. Among current users of estrogen therapy, those who were younger when beginning therapy had a decreased risk of breast cancer while there was an overall increase in breast cancer for older women on estrogen.

Comment

It is now accepted that breast cancer is the result of an accumulation of about 200 genetic mutations and that these mutations may be inherited, acquired following damage by irradiation or contact with carcinogens, by the action of viruses, or by spontaneously accidental mutations during cell division [2-5]. Spontaneous breast cell mutations are more frequent whenever cells are multiplying rapidly (as under the influence of estrogen). The accumulation of 200 or more mutations does not occur overnight. It is thought that it takes many years before a normal breast cell is converted into a cancer cell in-situ [2,3]. Once a cell acquires the genetic changes necessary to produce a malignant cell, further mutations to those extracellular proteins involved in tethering and maintaining cells in their designated position are required before a cancer in-situ becomes an invasive lesion.

The authors of this very large study have attempted to explain the vagaries of their results by hypothesizing on possible causes, but it is most likely that the anomalous findings obtained are the result of deficiencies in the study methodology rather than having a clinical significance. Criticisms of the methodology include:

1. The use of a structured half-hour telephone interview to obtain detailed information regarding medical history, hormone use, lifestyle and demographic factors. Even for women with a recent medical intervention, it is difficult to recall with accuracy the very important information regarding the use of hormones, chemotherapy or the complexities of surgical procedures – and this necessity for accurate memory would be particularly difficult for women in the control cohort, who may have had treatment or some important intervention 10 or more years previously. Although women in the breast cancer cohort generally have a good memory for surgical and hormone interventions, the same accuracy regarding past treatment or surgery cannot be assured for women in the control group.

2. The unsuitability of retrospectively comparing a cohort of women who had developed breast cancer with a cohort of women who did not have breast cancer (and who were recruited from driver licence or Medicare lists), as case–controls to determine whether the use of estrogen following oophorectomy, increased the risk of breast cancer. There is a strong genetic link between breast disease, bowel disease and ovarian disease [3,6], with cancer being one of the obvious associations. The cohort of women requiring gynecological intervention for ovarian or uterine disease is more likely to include a number of women who have pre-existing breast cell mutations. The presence of estrogen will invariably accelerate an increased risk of breast cancer in this cohort.

3. In reviewing the characteristics of the two groups, it is obvious that the women who developed breast cancer had a much stronger family history of breast cancer than did the control group (21.4% vs. 14.7%), indicating that these women were already genetically predisposed to early onset of breast cancer. A second possible adverse characteristic was the fact that women who developed breast cancer were more frequently overweight than the control cohort.

4. Although more than 80% of women in both groups had a history of mammogram screening, it is likely that the post-oophorectomy cohort had a more intense monitoring as a follow-up to receiving hormone therapy (thus detecting more early-stage cancers) than was conducted in the control group.

5. Case subjects were classified as having invasive breast cancer but no data were available as to the stage of the disease when first detected. It is known that about 30% of all women have marked cell atypia and cancer in-situ prior to their natural menopause [7,8], and it is also known that abnormal cells in these lesions will multiply faster in the presence of estrogen [9,10]. It would have been of interest to know whether the increased detection of breast cancer, in the first 10 years following initiation of estrogen therapy, was due to an increase in diagnosis of microinvasion or early-stage cancer due to intense monitoring of women receiving estrogen. If so, it would suggest that estrogen had increased the rate of cell multiplication in a pre-existing, pre-invasive lesion.

6. The disparate findings in this study suggest that the authors have 'trawled' through the mass of data they have accumulated in an effort to find some meaningful associations. They have produced several possible hypotheses to account for their disparate results.

7. The fact that oophorectomy in young women results in a reduced risk of breast cancer is the major outcome of significance in this large level-2 study. This confirms previous studies, suggesting that estrogen promotes the growth of unrecognized pre-invasive and microinvasive breast cancer [7,8] but, in spite of its huge size, the study fails to provide any details that will alter or influence the present clinical management of women following hysterectomy and bilateral oophorectomy.

In conclusion, one can agree with the sentiments expressed in the final sentence of the article that initiating estrogen therapy after total abdominal hysterectomy with bilateral oophorectomy at age 45 and older may increase the risk of promoting growth of a microinvasive or early-stage breast cancer. But, if there has not been a prior accumulation of the large number of cell mutations necessary for breast cancer, then the use of estrogen will not induce an increased risk [9,10].

Barry Wren

Gynaecological Endocrinologist, Edgecliff Centre, Edgecliff, NSW, Australia

References

1. Nichols HB, Trentham-Dietz A, Newcomb PA, et al. Postoophorectomy estrogen use and breast cancer risk. Obstet Gynecol 2012;120:27-36. http://www.ncbi.nlm.nih.gov/pubmed/22914389 

2. Hanahan D, Weinberg R. The hallmarks of cancer. Cell 2000;100:57-70. http://www.ncbi.nlm.nih.gov/pubmed/10647931 

3. Sjoblom T, Jones S, Wood LD, et al. The consensus coding sequence of human breast and colorectal cancers. Science 2006;314:268-74.  http://www.ncbi.nlm.nih.gov/pubmed/16959974 

4. Perez-Losada J, Gonzalez-Sarmiento R. Breast cancer: a stem cell disease. Curr Stem Cell Res Ther 2008;3:55-65. http://www.ncbi.nlm.nih.gov/pubmed/18220924 

5. Skinner M. Stem cells: insights into breast cancer heterogeneity. Nature Rev Cancer 2010;10:163-71. 6. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast cancer. Nature 2012; 23 September. Epub ahead of print.

7. Nielsen M, Thomsen JL, Primdahl S, et al. Breast cancer and atypia among young and middle aged women: a study of 110 medico-legal autopsies. Br J Cancer 1987;56:814-19. http://www.ncbi.nlm.nih.gov/pubmed/2829956 

8. Welch HG, Black WC. Using autopsy series to estimate the disease 'reservoir' for ductal carcinoma in situ of the breast. Ann Intern Med 1997;127:1023-8. http://www.ncbi.nlm.nih.gov/pubmed/9412284 

9. Dew J, Eden J, Beller E, et al. A cohort study of hormone replacement therapy given to women previously treated for breast cancer. Climacteric 1998;1:137-42. http://www.ncbi.nlm.nih.gov/pubmed/11907916 

10. O'Meara ES, Rossing MA, Daling JR, et al. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst 2001;93:754-62. http://www.ncbi.nlm.nih.gov/pubmed/11353785 

Content updated 23 October 2012