By Mitzi Baker

Reviewed by Miriam Komaromy, MD
Last updated April 6, 2001

Women with mutations in BRCA1 or BRCA2 have more than triple the risk of developing breast cancer compared with women in the general population. Not only is their risk higher, but some research shows that breast tumors in these women tend to behave differently than tumors in other women. Doctors are trying to understand all of those differences — and what they mean in terms of how the cancer progresses — so they can pick the most appropriate treatment strategy for each woman.

What Determines Breast Cancer Prognosis?

• Make too much or too little of certain cancer-related proteins
• Contain receptors for hormones such as estrogen or progesterone
• Develop in different regions of the breast
• Have spread to other regions of the body
• Are different sizes

These differences can tell a doctor quite a bit about how aggressive that tumor is likely to be, how likely it is to come back after treatment, and what drugs it will respond to. For example, tumors that contain mutations in certain cancer-related genes – notably HER2 or p53 – tend to be more aggressive and require more intensive treatment. Similarly, tumors that have spread to the lymph system or are quickly dividing tend to be more aggressive.

Researchers have noticed some trends in prognosis and tumor characteristics that may help them better treat women with BRCA1 or BRCA2 mutations.

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Breast Cancer Prognosis in Women With BRCA1 Mutations

Most studies suggest that survival for women with BRCA1 mutations is similar to or worse than that of women without the mutations. Ten recent studies comparing survival of women with BRCA1-postive and BRCA1-negative breast cancer have had inconsistent results:

• Five of the studies have not found any real differences.
  
• Two found slightly better prognoses.
  
• Three found worse prognoses

Of these ten studies, one included substantially more women than the others. It found a significant difference in breast cancer survival between Ashkenazi Jewish women with or without BRCA1 mutations. (Women of Ashkenazi Jewish descent are more likely to have mutations in BRCA1 and BRCA2 than women in different population groups.) During five years of the study, half of the 16 women with BRCA1-associated breast cancer had died after five years. Only nine percent of the 99 women without the mutation died during the five years. In this study, the woman's BRCA1 status was the only factor that could be used by itself to predict survival.

More on Breast Cancer in the Ashkenazi Jewish Population

The researchers emphasize that although their study is more conclusive than those previous, only 16 women had BRCA1 mutations. Their results should be regarded as preliminary and need to be confirmed in a much larger group of women.

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Breast Cancer Prognosis in Women With BRCA2 Mutations

Even less is known about breast cancers in women with BRCA2 mutation. The most informative study yet found that women with BRCA2-associated breast cancer have a similar prognosis when compared to women BRCA1-associated breast cancer or women without the mutations. The only major difference that showed up in this small study of 28 women was that tumors occurring in both breasts (called contralateral breast cancer) occurred five times more frequently in the BRCA2 group.

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Tumor Pathology in Women With BRCA1 or BRCA2 Mutations

BRCA1-associated tumors usually have several different characteristics than other types of breast cancer tumors.

• Have the wrong number of chromosomes (aneuploidy)
  
• Have cells that aren't dividing properly
  
• Look less like breast cells
  
• Originate in the ducts of the breast
  
• Have more mutations in p53 — a tumor suppressor gene
  
• Lack estrogen and progesterone receptors
  
• Occur in a younger woman

Based on these characteristics of BRCA1-positive tumors, it is somewhat surprising that the survival of patients with BRCA1-associated breast cancer is not dramatically worse than in other women. However, these tumors often have some qualities that may balance out the unfavorable factors, including:

• They are often a type of tumor called medullary carcinoma, which have a better prognosis that some other types of breast tumors
  

More on Types of Breast Cancer

• They have few immune cells within the tumor, and tend not to invade the lymph system
  
• They are less likely to make too much of the HER2 protein
  
• They have few blood vessels within the tumor, which means that the tumor receives less oxygen and other nutrients

Researchers think that the function of BRCA2 is very similar to that of BRCA1, so they assume that many of the findings for BRCA1-associated tumors will hold true for BRCA2. One difference that researchers have noticed is that tumors in women with mutations in BRCA2 are more likely to contain estrogen receptors than tumors in women with BRCA1 mutations. Tumors that contain estrogen receptors respond better to some drugs, such as tamoxifen and Femara. However, tumors in women who have mutations in either gene are still less likely to contain estrogen receptors than in women of the same age but without the mutations.

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More on Tamoxifen in Women With BRCA1 or BRCA2 Mutations

The Next Steps

At this time, there is no standard treatment for breast cancers in women with BRCA1 or BRCA2 mutations. However, as researchers learn more about how tumors progress in BRCA1-associated or BRCA2-associated tumors, they hope to be able to target treatments more effectively. In order to have this information, researchers will need to do large prospective studies, which follow the lives of women for many years after they have been diagnosed as having BRCA1 or BRCA2 mutations. In addition, studies to date have not included men – whose risk of developing breast cancer increases from around one percent to somewhere between four and 14 percent if they have a mutation in BRCA1 or BRCA2.

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References

Chappuis, P. O. et al. (1999). The influence of familial and hereditary factors on the prognosis of breast cancer. Annals of Oncol 10:1163-1170.

Donegan, W. L. (1997). Tumor-related prognostic factors for breast cancer. CA Cancer J Clin 47:28-51.

Foulkes, W. D. et al. (2000). Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome. Annals of Oncol 11:307-313.

Johannsson, O. T. et al. (1998). Survival of BRCA1 breast and ovarian cancer patients: A population-based study from Southern Sweden. J Clin Oncol 16:397-404.

Marcus, J. et al. (1996). Hereditary breast cancer: Pathobiology, prognosis, and BRCA2 and BRCA2 linkage. Cancer 77:697-709.

Phillips, K. A. et al. (1999). Breast carcinomas arising in carriers of mutations in BRCA1 or BRCA2: Are they prognostically different? J Clin Oncol 17:3653-3663.

Tirkkonen, M. et al. (1997). Distinct somatic genetic changes associated with tumor progression of carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Research 57:1222-1227.

Verhoog, L. C. et al. (1999). Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol 17:3396-3402.