Clinical Research Updates

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 could not identify large missing or rearranged portions of BRCA1 or BRCA2 genes. In 2002, a test that could identify five large changes in the BRCA1 gene was developed and has since been included in the full sequence testing of BRCA. In September 2006, a test that can identify additional large changes in both the BRCA1 and BRCA2 genes became available.

Who should consider this testing?

If you received genetic testing for mutations in the BRCA1 and BRCA2 genes at Memorial Sloan-Kettering prior to September 2006 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. 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.

What is the likelihood that the additional testing will 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 additional test. 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 this testing is $660.

Will insurance cover the cost?

Because the test is relatively new, it is unclear whether insurance will cover the fee. However, we have been successful in recovering costs for the test in patients with features of hereditary breast and ovarian cancer.

How do I learn more about this testing?

If you would like to discuss the improved BRCA testing with respect to your family history, we encourage you to speak with us. Please call the Clinical Genetics Service at Memorial Sloan-Kettering at 646-888-4050.

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 basic reason being that the gene had not been identified at the time the testing was conducted. Also, in the past, genetic testing has not been able to identify certain types of mutations, especially when large portions of a gene were missing or rearranged.

Improvements in testing have been made, and large changes can now be identified in a number of genes, including the following:

• p53 gene (Li-Fraumeni syndrome)
• STK11 gene (Peutz-Jeghers syndrome)
• MEN1 gene (multiple endocrine neoplasia type 1)
• MLH1, MSH2, and APC genes (hereditary colon cancer syndromes)

If you would like more information about testing for hereditary cancer syndromes, we encourage you to speak with one of our genetic counselors. Please call the Clinical Genetics Service at 646-888-4050 to make an appointment.

Recent improvements in testing for hereditary colon cancer have allowed large changes in the MLH1, MSH2, and APC genes to be identified.

In addition, three colon-cancer-predisposing genes -- PMS2, MSH6, and MYH -- have recently been identified, and testing for mutations in those genes is now 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, and APC, or for mutations in the newly identified genes PMS2, MSH6, and MYH.

If you would like more information about testing for hereditary colon cancer, we encourage you to speak with one of our genetic counselors. Please call the Clinical Genetics Service at 646-888-4050 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 conducted at Memorial Sloan-Kettering.

Women with BRCA mutations or strong family histories of breast cancer have relied on mammograms for early detection. But nearly half of all breast cancers in women at high risk 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 method 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 conducted at 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. These studies have brought to light 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.

At Memorial Sloan-Kettering, we recommend that an MRI be performed six months after a woman's annual 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, and it is important to note that we continue to detect some cancers by mammogram that were not seen on MRI six months earlier. For instance, some cancers, especially ductal carcinoma in situ (DCIS), are detected as flecks of calcium in the breast, and mammography is very good at showing calcifications that may not be seen as well by MRI.

It is important to note that MRI cannot detect all breast cancers. Also, MRI may detect masses that turn out not to be cancer, what are called false-positive results. To reduce the risk of false positives in premenopausal women, MRI should be performed in the second week of the menstrual cycle. MRI should 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 its limitations, however, it is not yet ready for use in women at lower levels of risk. Research at Memorial Sloan-Kettering aims to improve the usefulness of this technique.

We have recently conducted a review of cancer incidence in 165 families with three or more breast cancer cases but no BRCA1 or BRCA2 mutation detected. The study showed a markedly increased risk for breast cancer among women in these families, but no increased risk for ovarian cancer. The findings support our hypothesis that most 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 to undergo risk-reducing surgery for women who have tested negative for BRCA1 and BRCA2 mutations and do not have a family history of ovarian cancer.

If you would like more information, we encourage you to speak with one of our genetic counselors. Please call the Clinical Genetics Service at 646-888-4050 to make an appointment.

Recent studies conducted in Europe have shown that mutations in a gene called CHEK2 can slightly increase the risk of breast cancer. In response to these studies, we tested our population of patients in New York City for this particular mutation of CHEK2. 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 twofold. (BRCA1 mutations increase the risk for early onset breast cancer more than 20-fold.) We did not find an increased risk of ovarian cancer, lymphoma, or colon cancer associated with the CHEK2 mutation.

Typically, testing for BRCA mutations begins when an individual receives a diagnosis of breast or ovarian cancer. Knowing whether there is a BRCA mutation in the family allows family members to more accurately assess their own risk. If a living relative affected by breast or ovarian cancer is not available for testing, testing may still be performed. In 2007, Memorial Sloan-Kettering Cancer Center made available BRCA testing of stored tissue samples obtained at the time of a biopsy or surgery. The samples are referred to as paraffin samples because the tissues are stored in paraffin wax. The paraffin samples are typically maintained in pathology departments; however, the length of time samples will be kept may vary. For individuals of Ashkenazi Jewish ancestry, it is possible to test DNA from paraffin samples for specific mutations. A discussion of how to carry out genetic testing of paraffin samples can take place at the time of genetic counseling.

Recent research led by investigators from the Clinical Genetics Service at Memorial Sloan-Kettering indicates that preventive removal of the ovaries, called oophorectomy, may have a greater impact on reducing breast cancer risk for women with BRCA2 mutations than for women with BRCA1 mutations, though oophorectomy did offer women with BRCA1 mutations protection against ovarian and fallopian tube cancers after preventive ovary removal. If confirmed, these findings will allow physician to better tailor risk-reduction approaches for women at inherited risk of breast and gynecologic cancer.

The Clinical Genetics Service at Memorial Sloan-Kettering has documented the frequency of a particular mutation in MSH2, called A636P, in individuals of Ashkenazi ancestry at risk for colon cancer. This mutation appears to be the most frequent genetic alteration noted in families with marked histories of colon, uterine, and other cancers. Such families meet criteria for Lynch syndrome, also called hereditary non-polyposis colon cancer. Testing for the MSH2 A636P mutation is generally included as advised at the time of genetic counseling and risk assessment for hereditary colorectal cancer.

In a study of women referred to the Clinical Genetics Service for evaluation of a family history of breast cancer, those with ductal carcinoma in situ (DCIS) were as likely to have a BRCA mutation as those with invasive cancer. These results point to a need in clinical practice to take a family history of DCIS as seriously as a family history of invasive breast cancer.

Pre-implantation genetic diagnosis is a technique allowing for the selection of embryos that do not carry specific genetic mutations associated with disease risk. This technique, called PGD, does not involve amniocentesis or pregnancy termination. PGD has been performed for women who are at risk for a number of hereditary genetic disorders, including for common hereditary cancer syndromes.

If you would like more information about PGD, we encourage you to speak with one of our genetic counselors. Please call the Clinical Genetics Service at 646-888-4050 to make an appointment.

The Research Laboratory of the Clinical Genetics Service at Memorial Sloan-Kettering has been active in performing genome-wide association studies (GWAS), and in 2008 we published one of the early GWAS studies addressing genetic risks for breast cancer. Our study, and a number of other GWAS results, have defined potential new genetic markers associated with risk for breast, colon, prostate, and other cancers. Given the very low risks associated with these markers, it is unclear at the present time whether they will be useful in guiding decisions regarding prevention and early detection. For example, the risks associated with most of these markers confer a 1.2- to1.4-fold risk of cancer, compared with up to 50-fold for mutations of genes such as BRCA. Nonetheless, these studies offer promise for discovering new pathways associated with cancer formation, progression, and response to disease.

In collaboration with medical oncologist Manish Shah and Robert Kurtz, Chief of the Gastroenterology and Nutrition Service, several genetic counselors on the Memorial Sloan-Kettering Clinical Genetics Service have begun to offer genetic counseling and testing to families affected by a diffuse form of stomach cancer as well as to families affected by pancreatic cancer.

In addition to this registry, a new program has been created to enroll families with a history of bladder cancer. Also, Kenneth Offit, Chief of the Clinical Genetics Service, continues to enroll families with multiple cases of cancer of the blood and lymph system, including Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, and chronic lymphocytic leukemia. Already, some genetic markers associated with risk for these diseases have been found.