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Prof. Roland Holland: Breast Cancer Risk and Genetics —
Pathological considerations

Of the approximately 180,000 breast cancers in the USA in 2007, somewhere between 5 % and 10 % were caused by a highly penetrant cancer susceptibility gene. Only a few of these individuals were known mutation carriers before the diagnosis, when this knowledge might have prevented the cancer or led to an earlier diagnosis. Many of these cancers were not even identified as “hereditary” even after the diagnosis, when this knowledge might have changed their management or helped other family members who are still at risk.

To address these issues of risk management and prevention, the sixth international consensus conference of the Breast Health Institute was convened in Philadelphia, in April 2007 inviting a group of experts in breast cancer care, cancer genetics and risk assessment. The goal was to summarise the state of the art in terms of identification of patients at high risk and to discuss the various management strategies appropriate to level or type of risk.

Risk should be expressed both in absolute terms, and compared to an “average” woman in the patient’s age group (relative risk or RR). The “average” woman in the United States has a 1 in 8 risk of breast cancer over her lifetime. In the Netherlands this figure approaches 1 in 7. “Risk factor” means any variable that increases the risk of breast cancer for those that have it compared to those who do not. Major risk factors are usually regarded as those which are responsible for more than a two fold increase in risk whereas minor factors are associated with a relative increase between 1 and 2.

The Panel agreed to six basic categories of risk from average to very high risk and gave recommendations for management strategies by categories.

The Dutch Guidelines lists 20 different risk factors together with their relative risk and gives different management recommendation by factors with RR less and more than 4.

Pathological considerations:

  • The presence of LCIS, ADH or ALH on prior biopsy conveys moderately elevated risks (RR 4- to 5-fold), yet pathologists are unable to consistently recognise these entities.
  • Mutations in BRCA1 and BRCA2 markedly increase the risk of both breast (at least 60% life time risk) and ovarian cancer (15% to 40% lifetime risk) and are responsible for about 45% of families with multiple cases of breast cancer and up to 90% of families with both breast and ovarian cancer. Associated cancers differ in various aspects. BRCA1 carriers are of younger age, their tumours likely to be of high grade, of medullary type histology and so-called “triple negative”: ER/PR and Her-2 negative. Tumours of BRCA2 carriers are more likely of intermediate grade, of IDC type and ER/PR positive. Male carriers with either mutation seem to be at an increased risk for carcinoma of the prostate as well as breast, modestly increased with the BRCA1 mutation but with at least double lifetime risk for carriers of the BRCA2 mutation
  • For BRCA1 or BRCA2 mutation carriers there are two major choices with respect to management of each organ at risk, namely lifetime follow-up with or without chemo-prevention agents, or risk reduction surgery, that is bilateral total mastectomy and prophylactic oophorectomy. Premenopausal oophorectomy lowers the lifetime risk of breast cancer by about 50% in mutation carriers.
  • Mutation carrier with breast cancer can be safely treated by breast conservation, expecting about the same in breast recurrence rate as a non-carrier initially, though likely having a higher rate after about 5 to 10 years. Bilateral breast MRI should be performed prior to any surgery, to identify multicentric disease or occult contralateral cancer.
  • A number of other, pathology related issues of patient management will be discussed.