Clinical Research Updates 2005-2006

Genetic testing does not always identify mutations, even when the family history suggests that an inherited predisposition to cancer is likely. For example, in the past genetic testing for BRCA1 and BRCA2 was not able to identify any large missing or rearranged portions of the gene. A test was developed in 2002 that could identify five large changes in the BRCA1 gene and has since been included as part of the BRCA full sequence testing. Now, a new test has become available that can identify additional large changes in both the BRCA1 and BRCA2 genes.

Who should consider this testing?

If you had genetic testing for mutations in the BRCA1 and BRCA2 genes before September 2006 at Memorial Sloan-Kettering and the results were negative or uninformative (no mutation or an "uncertain variant" was identified), you may benefit from learning more about the new testing for additional large changes in these two genes. Note that this testing is not applicable for individuals who have tested negative for a specific mutation already known to be present in his or her family. Also, this test will not be routinely included in BRCA1 and BRCA2 genetic testing in the future, except for those with very strong family histories of breast and/or ovarian cancer.

What are the criteria which the testing lab now uses to decide if the new testing will be performed?

*At least one relative must be a first (parent, sibling, child) or second (aunt, uncle, grandparent) degree relative

How often does the new testing find mutations?

A small number of individuals with significant family histories of breast and ovarian cancer are expected to have a BRCA1 or BRCA2 mutation detected by the new test. However, the more relatives with breast and ovarian cancer there are in a family, the greater the chance the test will be positive.

How much does the test cost?

The current cost of the additional testing is $660.

Will insurance cover the cost?

Because this test is so new, it is unclear whether or not insurance will cover this fee.

How do I learn more about this testing?

If you would like to discuss the improved BRCA testing in relation to your family history, we encourage you to speak with us. Please call the Clinical Genetics Service at 212-434-5149.

Genetic testing does not always identify mutations, even when the family history suggests that a predisposition is likely to be present. There are a number of reasons for this. One reason is that, in the past, genetic testing was not able to identify genes that had large portions missing or rearranged. There have been improvements in testing, and these large changes can now be identified in the MLH1, MSH2, and APC genes. Testing may also be negative (despite a strong family history) if the predisposition is due to genes that were not known at the time the testing was done. Two recently identified colon cancer predisposing genes are MSH6 and MYH. Testing for mutations in these genes has now become available.

If you had genetic testing for hereditary colon cancer prior to November 2004, and the results were negative, you may benefit from testing for previously undetectable mutations in MLH1, MSH2, or APC, or for mutations in the "new" genes MSH6 or MYH. If you would like to discuss this further, we encourage you to come and speak with us. Please call the Clinical Genetics Service at 212-434-5149 to make an appointment.

Several recent studies have suggested that breast magnetic resonance imaging (MRI) is probably helpful to women at high risk for breast cancer. This confirms earlier work done at Memorial Sloan-Kettering.

Women with BRCA mutations or strong family histories of breast cancer have relied on mammograms to find breast cancer early. But nearly half the breast cancers detected in these women are found as breast lumps within 12 months of a normal mammogram. There are several reasons for this. Younger women often have dense breasts, which are harder to examine by mammography. Also, breast cancers in these women tend to grow quickly.

Until recently, breast ultrasound was the only alternative screening for breast cancer in women at high risk. While ultrasound does find some cancers not picked up by mammogram, the incremental benefit of ultrasound in women with BRCA mutations appears to be small.

A number of studies, including one from Memorial Sloan-Kettering, suggest that breast MRI may be able to find cancers missed by either mammogram or ultrasound. Several larger studies have confirmed this.

• In one study from the Netherlands, over 1,900 women (358 mutation carriers) were screened each year with mammogram and MRI. Over 70 percent of the cancers were detected by MRI compared with only 40 percent by mammography. [PubMed Abstract]
• In a second study, from Canada, 236 mutation carriers were screened yearly with mammogram, MRI, and ultrasound. Of the cancers diagnosed in this study, 77 percent were detected by MRI compared with 36 percent by mammogram and 33 percent by ultrasound. [PubMed Abstract]

How have these studies changed our practice? First, they have brought home the limitations of mammograms in women at hereditary risk. For this reason, we recommend that women at hereditary risk (those with BRCA mutations or very strong family histories of breast and/or ovarian cancer) have an MRI performed each year.

We perform the MRI 6 months after the mammogram to try to catch fast-growing cancers in mid-year. Other centers perform MRI and mammograms at nearly the same time. It is not clear which schedule is better. It is important to note that we continue to detect some cancers by mammogram that were not seen on MRI 6 months earlier. Some cancers, especially DCIS (ductal carcinoma in situ), are detected as flecks of calcium in the breast. Mammography is very good at showing calcifications, which may not be seen as well by MRI.

It is important to note that MRI is not perfect. Some of breast cancers may be missed by MRI. MRI may detect masses that turn out not to be cancer (false-positives). To reduce the risk of false-positives, MRI should be performed in the second week of the menstrual cycle (for premenopausal women). MRI should also be performed at a center experienced with these types of studies.

Although not perfect, screening breast MRI is a step forward for women at hereditary risk for breast cancer. Because of the limitations, however, it is not yet ready for use in women at lower levels of risk. Research continues at Memorial Sloan-Kettering to improve the usefulness of this technique.

Risk for Ovarian Cancer in Women
Who Tested Negative for BRCA Sequencing

We have recently reviewed the cancer incidence in 165 families with three or more breast cancer cases but no BRCA1 or BRCA2 mutation detected. This study showed that there was a markedly increased risk for breast cancer, but no increased risk for ovarian cancer in these families. These findings support our impression that most of ovarian cancer occurring with breast cancer in the same family is linked to BRCA1 and BRCA2. These findings may have implications regarding the need to participate in intensive ovarian surveillance or undergo risk-reducing surgery for women who have tested negative for BRCA1 and BRCA2 mutations and who do not have a family history of ovarian cancer. For further information, and to schedule an appointment to discuss this information please call 212-434-5149.

New 'Low-Risk' Genetic Markers for Breast Cancer

Over the past several years, studies in Europe have shown that mutations in a gene called CHEK2 can slightly increase the risk of breast cancer.

• We looked for the common European mutation of CHEK2 in our population of patients in New York City. We observed it at a very low frequency and concluded that it was not clinically relevant to our population.
• We have also identified another mutation of CHEK2 in individuals of Ashkenazi Jewish ancestry. This mutation called S428F was found to increase cancer risk approximately 2-fold. BRCA1 mutations increase the risk for early onset breast cancer over 20-fold; whereas the risk for breast cancer in those carrying the S428F CHEK2 mutation was only 2-fold. We did not find an increased risk of ovarian cancer, lymphoma, or colon cancer with the CHEK2 mutation.

Lymphoma Research and Other Areas

There continues to be numerous other active areas of research within the Clinical Genetics Service.

• We are continuing with our study of familial predisposition to lymphomas. We have recently identified genetic markers that appear to be associated with early onset of a diffuse non-Hodgkin's lymphoma in young women.
• In the area of genetic research involving individuals of Eastern European (Ashkenazi) Jewish ancestry, a large effort is underway to identify new cancer susceptibility genes. Experiments are underway to map new breast cancer susceptibility genes in families that test negative for BRCA1 or BRCA2 mutations
• We hope to make clinically available over the next year testing for the three 'Ashkenazi' BRCA mutations in tumor blocks from deceased relatives with cancer. As this testing becomes available, it will be noted on this Web site.
• We are also completing our large study of families with colon cancer. As mentioned above, we have confirmed the presence of mutations in the genes MSH6 and MYH in some families. We are continuing to look for other colon cancer predisposing genes that may be mutated in families.