Peutz-Jeghers syndrome

The last few years' advances in the field of hereditary breast cancer genetics have altered clinical practice. It is generally accepted that the process of carcinogenesis is caused by the serial acquisition of multiple genetic mutations within one or more cells, ultimately leading to the malignant phenotype. The cause of this initial genetic error differentiates hereditary cancers from sporadic cancers. Only 5-10% of cancers are primarily caused by genetic mutations inherited in the germline. However, due to the high penetrance and autosomal dominant nature of inherited genetic mutations, hereditary cancer families have been identified, leading to the rapid localization and cloning of several predisposing cancer genes.

Although only 5-10% of breast and ovarian cancers are hereditary,1 this accounts for approximately 20,350 breast cancers and 2,330 ovarian cancers diagnosed in the United States. Hereditary mutations influence cancer risk but are not one hundred percent penetrant. The subsequent environmental and/or genetic factors influencing the cell's progressive malignant development are largely unknown. Many patients are believed to be at increased risk for cancer. Physicians and healthcare specialists often refer these patients for risk assessment and recommendations for preventive risk-reducing strategies.

CANCER GENETIc COUNSELING

Cancer genetic counselors often take on the primary role in relaying new medical information to patients, assessing cancer risk, and offering options for cancer genetic testing and medical management strategies. Because of rapid advances in cancer genetics, the cancer genetic counselor has become essential to a comprehensive multidisciplinary cancer program.2

BREAST AND OVARIAN CANCER SYNDROME (BOCS)

BOCS is largely accounted for by deleterious BRCA1 or BRCA2 gene mutations. Those genes normally function as tumor suppressors; however, when a deleterious BRCA germline mutation is present, the risk of cancer increases, causing the BOCS. Approximately 16% of mutations in families with hereditary breast cancer are not found by standard BRCAl and BRCA2 DNA sequencing and are believed to be caused by either an undiscovered gene or mutations within BRCAI and BRCA2 that are missed by the current testing methods.3 Additionally, less common hereditary breast cancer syndromes can be recognized by associated clinical characteristics and confirmed with molecular testing; e.g., Cowden syndrome, Bloom syndrome, Peutz-Jeghers syndrome, Werner syndrome, Xeroderma Pigmentosum, Ataxia-Telangiectasia and Li-Fraumeni syndrome. Similarly, there are other syndromes associated with hereditary epithelial ovarian cancer such as Hereditary Nonpolyposis Colon Cancer (HNPCC).

Guidelines from the American Society of Clinical Oncology (ASCO) recommend that three conditions be met before offering genetic testing; 1) a likelihood > 10% of a positive test; 2) genetic test results that can be adequately interpreted and 3) results that will influence medical management.4 Because many more families have undergone BRCA gene testing, more accurate carrier assessments can now be constructed; and the ASCO is revising their guidelines, slated for publication in 2005.

BRCA1 AND BRCA2 CANCERPREDISPOSING MUTATION PROBABILITY

Overall, studies indicate that a BRCA1 or BRCA2 cancer-predisposing gene mutation is more likely present if family history includes: breast cancer diagnosed before age 50 years, bilateral breast cancer, ovarian cancer, Ashkenazi Jewish ancestry, or the occurrence of both breast cancer and ovarian cancer in the same woman.5-9 [The "family history" depends on the size of the family, the age of cancer diagnosis and type of primary cancer - any unusal pattern, young onset cancers, multiple primaries, syndromic cancer constellation in any family members would be of concern, including uncles and cousins.] Because each study evaluated BRCA carrier risk from a selected population, it is often best to determine an individual's/family's carrier probability according to the data set that is clinically most similar or applicable.

A software model (BRCAPRO) calculating the probability for the presence of a cancer-predisposing BRCAI or BRCA2 mutation has been developed. This calculation is based on observations in referral populations in which the majority of women tested were affected with breast or ovarian cancer.8,10 BRCAPRO adjusts risk according to bayesian theorem, however, it may over or under estimate carrier risk depending on the familial characteristics.

Due to vast familial cancer variability, it is recommended that hereditary cancer risk assessment be performed by experienced clinicians to assure the most accurate assessment, in accordance with the most applicable data set(s).

CANCER RIsKS ASSOCIATED WITH A BRCA DELETERIOUS MUTATION

The majority of hereditary breast and ovarian cancer (HBOC) families have been linked to gene mutations affecting the normal function ofthe BRCAI or BRCA 2 protein. Women carrying a deleterious BRCA gene mutation have a 56% to 85% cumulative lifetime risk of developing breast cancer up to age 70,(11,12) and a 27%13 to 44%14 cumulative lifetime risk of ovarian cancer. Additionally, male BRCA heterozygotes carry an approximate 6% male breast cancer risk by age 70, and a 3 to 4 fold increase relative risk of prostate cancer by the age of 80.(15) Although low, the risk of pancreatic cancers in men and women carrying a BRCA2 mutation was estimated to be approximately 2 to 3% by age 80.(15) There remains suggestive (but not substantiated) evidence of additional cancer risks influenced by an absent BRCA protein, such as colorectal cancer and melanoma.

MANAGEMENT OF RISK IN CARRIERS OF BRCA GENE MUTATIONS

Management of individuals found positive for hereditary breast and ovarian cancer susceptibility syndrome includes discussion regarding cancer screening protocols, options for chemoprevention, as well as prophylactic surgery. Although a number of interventions have been postulated to reduce the morbidity and mortality from breast cancer in women confirmed to carry a BRCA1 or BRCA2 cancer-predisposing mutation,16 data are evolving to substantiate these claims. Nevertheless, several strategies have been prospectively studied and proven to detect early staged cancers in BRCA heterozygotes;17 e.g., cancer screening, prophylactic mastectomy and/or oophorectomy, and chemoprevention.

CANCER SCREENING

Recommendations for cancer screening of individuals with a BRCA1 or BRCA2 cancer-predisposing mutation have been made by a task force convened by the Cancer Genetics Studies Consortium (CGSC), an NIH-sponsored consortium of researchers assessing the ethical, legal, and social implications of genetic testing for cancer risk.16 The CGSC recommendations were based on presumed benefit and may change as new evidence becomes available; therefore, patients must be counseled regarding the limited knowledge about strategies to reduce risk. Furthermore, patient preference should be taken into account for follow-up decisions. Recommendations similar to those of the CGSC are practiced in 16 European family cancer centers.18

Breast Cancer Screening

The three-pronged breast cancer screening regimen is based on data from families with cancer-predisposing BRCA1 or BRCA2 mutations, addressing the elevated breast cancer risk beginning in a woman's late 20s or early 30s.16 Individuals predisposed to an inherited breast cancer risk are recommended to consider:

* Monthly breast self-examination starting at age 18 to 21.

* Annual or semi-annual clinical breast examination beginning at age 25-35 years

* Annual mammography beginning at age 25-35 years

There is evidence that BRCAl and BRCA2 gene products may be necessary to assist with DNA damage repair caused by radiation.19 Despite concern regarding the repeated low doses of radiation exposure in BRCA positive women, the Human Genome Research Institute's (NHGRI) task force states that this hypothetical risk would likely be outweighed by mammography's benefit on early cancer detection.20

Other breast imaging modalities are being studied in germline BRCA carriers. Early studies report that breast MRI may detect cancers in mutation carriers that were occult on both mammogram and clinical breast exam and, thus, a potentially promising screening devise for hereditary breast cancer families.21

Men with BRCA mutations may also be at increased risk for breast cancer, and evaluation of any breast mass or change is advisable; however, there is insufficient data to recommend a formal surveillance program at this time.16

Ovarian Cancer Screening

The ovarian cancer screening measures have limited sensitivity and specificity and have not been shown to reduce ovarian cancer mortality. Nevertheless, the CSGC16 and NHGRI task force recommends for women with a BRCA1 or BRCA2 cancer predisposing mutation the following:

* Annual or semi-annual pelvic examination beginning at age 25-- 35 years

Annual or semi-annual transvaginal ultrasound examination with color Doppler beginning at age 25-35 years

Annual or semi-annual serum CA-125 concentration beginning at age 25-35 years. Serum screening can be associated with a high false positive rate, especially in premenopausal women, and is often abandoned by physicians even in germline carrier screening.

The Memorial Sloan Kettering Cancer Center reports the first prospective evidence demonstrating that the above surveillance strategy employed in BRCA positive women may result in the diagnosis ofearly staged ovarian tumors.17

PROPHYLACTIC SURGERY

Prophylactic Mastectomy

In a study23 of 6039 women found to carry a BRCA gene mutation and/or with a family history of breast cancer who underwent prophylactic mastectomy, Hartmann et al estimated a 90- 94% reduction in breast cancer risk and an 81-- 94% reduction in breast cancer-related deaths. Additional prospective data on 251 BRCA positive individuals followed at Memorial Sloan-Kettering Cancer Center demonstrated the detection of two occult intraductal breast cancers within the 29 individuals choosing riskreducing mastectomy.17

Although only a small percentage of women from high-risk families choose to undergo prophylactic bilateral mastectomy, those who do generally feel content with their decision. In a follow-up study of high-risk women who pursued preventive surgery, approximately 74% reported a reduced emotional concern regarding breast cancer development and seemed to naturally sustain other psychological and social functioning.25

Prophylactic Oophorectomy

Data presented at the American Society of Human Genetics 50th Annual Meeting (2001) indicates that prophylactic bilateral salpingo-oophorectomy (BSO) reduces the risk of ovarian cancer by 95% in women with BRCA deleterious mutations. The risk of primary peritoneal carcinomatosis does not appear to be affected by salpingo-ophorectomy. The National Cancer Institute found that women from families at high risk for ovarian cancer had an equal rate of primary peritoneal cancer after oophorectomy compared to the rate of primary peritoneal cancer in women who had not had the procedure.26 Additional studies are necessary to investigate whether hysterectomy or any other strategy would further reduce the risk of primary peritoneal cancer post salpingoophorectomy.

Rebbeck et al27 also demonstrated that prophylactic oophorectomy reduces the risk of breast cancer by approximately 50% in BRCA carriers. Additionally, of 21 of 36 BRCA gene positive women diagnosed with breast cancer who underwent BSO either before or within 6 months of their cancer diagnosis, only 1 of 21 relapsed versus the 7 of 21 of women who retained their ovaries.28 Therefore, experts now suggest that BRCA heterozygotes consider risk-reducing prophylactic salpingo-oophorectomy to reduce the risk of both ovarian and breast cancers

As preventive oophorectomy become more common secondary to the identification of an inheritable mutation, specific recommendations are emerging related to the surgical procedure, as well as regarding pathologic examination of the tissue removed. Unexpected gynecologic neoplasms were discovered in five high-risk breast/ovarian cancer patients (4 of the 5 patients had a documented deleterious BRCA mutation) who underwent prophylactic salpingo-oophorectomy with hysterectomy. Therefore, more rigorous tissue examination, as well as specified surgical interventions should be considered for the detection of early neoplastic changes when BRCA carriers choose preventive BSO as a risk-reducing strategy.29

After comprehensive cancer genetic counseling, the majority of women are pleased with their decision to pursue surgical interventions for ovarian cancer prevention. Although approximately 93% of high-risk women who underwent prophylactic oophorectomy expressed no regret about their decision, 50% preferred more information about the risk and benefits of hormone replacement therapy (HRT) prior to decisions about surgery.30 Thus, although counseling appears to addresses the direct surgical issues, more attention should be directed to the outcome implications.

CHEMOPREVENTION

Breast Cancer Risk Reduction

The national surgical adjuvant breast and bowel project (NSABP P-1) prevention trial assessed the treatment of tamoxifen (a partial estrogen antagonist) in women identified by the Gail model to have an increased breast cancer risk. This study reported a 49% reduction in breast cancer in the five-year group treated with tamoxifen. It was concluded that tamoxifen prophylaxis was most beneficial in women with an elevated risk of breast cancer who were under age 50, because premenopausal women did not seem to be at increased risk for venous thrombosis or uterine cancer when compared to their post- menopausal counterparts. However, tamoxifen reduced the incidence of breast cancers that were estrogen receptor-positive, but not estrogen receptor-negative. Since breast cancers occurring in women with BRCA1 mutations are more likely to be estrogen receptor-negative,28 it is difficult to estimate the benefit of tamoxifen prophylaxis without testing the effect in women with BRCA1 or BRCA2 cancerpredisposing mutations.

To assess the effect of tamoxifen in BRCA carriers, complete BRCA sequencing analysis was performed on 288 of the 315 women who developed invasive breast carcinoma.32 However, only 19 (6.6%) were found to be heterozygous for BRCA mutations. Due to the small sample and wide confidence intervals, conclusive data could not be drawn; but encouraging results from Narod et al.33 demonstrated an estimated 75% reduction for a contralateral breast cancer in BRCA1 and BRCA2 cancers.

Nevertheless, because tamoxifen treatment can have significant adverse consequences (a higher rate of endometrial cancer and thromboembolic episodes, including pulmonary embolism), patients should be counseled accordingly.

Ovarian Cancer Risk Reduction

One case control study found a significant decreased risk of ovarian cancer in women with BRCA1 or BRCA2 cancer-predisposing mutations who took oral contraceptives for more than three years.34 These data remain consistent with general population studies which indicate a reduced risk of somatic ovarian carcinoma with oral contraceptive use; but the study is debated, primarily because it did not assess other outcomes, such as the effect of oral contraceptives on breast cancer risk.

Our understanding of inherited and acquired genetic mutations that eventually give rise to the malignant phenotype is evolving. Still in its infancy, the discipline of cancer genetics will evolve more rapidly over the next 10 years with the newer techniques, such as DNA chip analysis and micro array processing, which will yield a better understanding of the genotype-phenotype relationship.

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Jennifer L. Scalia, MS, and Robert D. Legare, MD

Jennifer L. Scalia, MS, is Clinical Program Coordinator Cancer Risk Assessment and Prevention Program Women & Infants' Hospital.

Robert D. Legare, MD, is a medical oncologist at Women & Infants' Hospital; Medical Director, Cancer Risk Assessment and Prevention, Program; and Assistant Professor of Obstetrics & Gynecology, Brown Medical School.

CORRESPONDENCE:

Jennifer L. Scalia, MS

Women & Infants' Hospital

101 Dudley St.

Providence, RI 02905

phone: (401) 453-7540

fax: (401) 453-7785

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