All forms of breast cancer are thought to develop as a consequence of unregulated cell growth and the development of phenotypic changes such as the ability to invade, recruit a new blood supply, and metastasize. These changes in phenotypes result from the development of aberrations in genetic pathways. Some of these aberrations are inherited (germline mutations), whereas others develop during the life of a breast cell (somatic mutations). Most breast cancer is thought to be a consequence of a series of somatic mutations. Only 20% to 25% of breast cancer patients have a history of breast cancer in a first-degree relative. However, it is possible that some women without a first-degree relative with breast cancer still inherit a genetic background that predisposes to breast cancer. These mutations may be insufficient to cause breast cancer unless accompanied by other mutations and therefore would be predicted to have a low penetrance. Historically, it has been much more difficult to discover low-penetrance mutations than to discover germline mutations that result in an autosomal dominant pattern of breast cancer development. However, newer molecular techniques, such as deoxyribonucleic acid (DNA)–array assays and single nucleotide polymorphism (SNP) arrays, may help in the identification of low-penetrance predisposing mutations. Approximately 10% of breast cancer patients have familial breast cancer, typically defined as breast cancer showing an autosomal dominant inheritance pattern. During the 1990s, germline mutations in three important tumor suppressor genes—TP53, BRCA1,and BRCA2—were discovered in family members of individuals with familial breast cancer. All three genes have been shown unequivocally to predispose to breast cancer.

 

Germline Mutations in TP53

Germline mutations in the TP53 gene (formerly called p53 or LFS1) are rare and result inLi-Fraumeni syndrome, named after two investigators who made significant contributions to the understanding of this condition. TP53 is one of the most important tumor suppressor genes and has been called the “guardian of the genome” because of its critical role in cellular pathways that recognize and direct a response to DNA injury. TP53 regulates the transcription of several important genes. Through its regulation of CDKN1A (formerly called p21, CIP1, or WAF1), GADD45A (formerly called GADD45), and other genes, TP53 can promote cell cycle arrest after DNA injury, allowing cells sufficient time for DNA repair before S phase, G2, and mitosis. Alternatively, through regulation of the BCL2 family of genes, TP53 can direct a cell toward apoptosis to prevent propagation of damage to progeny cells. One consequence of a germline mutation in TP53 is cancer development. Individuals with Li-Fraumeni syndrome are at increased risk for a variety of types of cancer, including childhood sarcomas, gynecologic tumors, and breast cancer. Breast cancer is the most common malignancy in patients with Li-Fraumeni syndrome; the lifetime risk is estimated to be 90%.

 

Germline Mutations in BRCA1 and BRCA2

Studies of patients with familial breast cancer led to the discovery of BRCA1 in 1990 andBRCA2 in 1996. Like TP53, BRCA1 and BRCA2 are tumor suppressor genes that contribute to the stability of the genome by mediating the effects of the cellular response to DNA injury. The BRCA1 and BRCA2 proteins have important roles in processing double-stranded DNA damage. The proteins encoded by these genes colocalize with RAD51 to form a complex important in the repair of double-strand breaks. BRCA1 also participates in transcription-coupled repair, homologous repair, and end-rejoining. One consequence of loss of function of BRCA1 or BRCA2 is increased radiosensitivity, which is directly related to dysregulation of the double-stranded DNA damage pathway.Individuals with a germline mutation in BRCA1 have a lifetime risk of breast cancer of 65% to 85%. These individuals have a lifetime risk of ovarian cancer approaching 50%. Other types of cancer that develop more frequently in BRCA1 carriers include colon cancer and prostate cancer. The lifetime risk of breast cancer for women with germline BRCA2 mutations mirrors that for women with BRCA1 mutations. BRCA2 mutation carriers are also at increased risk for ovarian cancer compared with the general population, but their risk is much less than the risk for women with BRCA1 mutations. BRCA2 is also associated with male breast cancer. Genetic screening for germline mutations in BRCA1 and BRCA2 is possible and is increasing in frequency for women with strong family histories of breast cancer or ovarian cancer, or both. Testing should be performed only at centers that have genetic counseling programs designed to properly inform individuals of the social, economic, and legal consequences associated with genetic testing. Germline mutations in BRCA1 and BRCA2 are rare, occurring in fewer than 7% of patients with breast cancer. Only a few breast cancer patients with a family history of the disease are predicted to carry a mutation in one of these genes. Table 17-3 contains data concerning the probability of carrying a BRCA1 mutation based on an individual’s age at cancer diagnosis, personal cancer history, and family cancer history and whether the individual is of Ashkenazi Jewish descent.68 Treating physicians and patients have consistently been found to overestimate the probability of having a germline mutation in a BRCA gene. 

 

TABLE 17-3 Probability of BRCA1 Germline Mutations in Various Clinical ScenariosData from Shattuck-Eidens D, Oliphant A, McClure M, et al. BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 1997;278:1242-1250.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

No definitive data exist on which to base screening recommendations for individuals with a proven germline mutation in a gene predisposing to the development of breast cancer. The American Society of Clinical Oncology published a consensus statement recommending that such individuals undergo annual mammography and clinical and self-breast examination beginning at the age of 25 to 35 years. Annual pelvic examinations with transvaginal sonography, color Doppler examinations of the ovaries, and measurement of serum cancer antigen (CA) 125 levels also are recommended beginning at age 25 to 35 years. The use of magnetic resonance imaging (MRI) to screen for breast cancer in young women with a known BRCA mutation has gained interest. In one nonrandomized study of 236 women with a known BRCA mutation who underwent screening with mammography, sonography, MRI, or some combination of these three modalities suggested that MRI screening had a higher sensitivity for detecting breast cancers than the other radiographic modalities or physical examination alone. The American Cancer Society now recommends that MRI be used in conjunction with mammography for screening in women with a known BRCA mutation.

 

Breast Cancer Biology

Breast cancer is a heterogeneous set of diseases. Advances in genomics and molecular biology have provided insights into the genetic heterogeneity of breast cancer and how this heterogeneity affects clinical outcome. Using DNA microarray technology, Perou and colleagues described a molecular classification scheme for breast cancer based on the genomic expression of the tumor, and several groups subsequently reproduced those results. The classifications, which largely reflect molecular signals in the estrogen receptor and ERBB2 (also called HER2/NEU) signaling pathways, represent four broad groups: luminal A and luminal B cancer (two predominantly estrogen receptor–positive classes with distinct biologic outcomes); basal-like cancer (which is predominantly estrogen receptor–negative and HER2/NEU–negative), HER2/NEU-positive cancer, and cancer with gene expression patterns that mimic those of the normal breast.

 

Breast Cancer Prevention Strategies

Tamoxifen

One of the most exciting areas of breast cancer research is breast cancer prevention. Increasing knowledge of the role of estrogens and progesterones in breast cancer development has led to the development of pharmacologic strategies that could significantly reduce the incidence of breast cancer over the next 2 decades.Interest in tamoxifen as a chemopreventive agent arose after several randomized trials designed to test the efficacy of hormonal therapy for invasive breast cancer reported that tamoxifen reduced the incidence of contralateral breast cancer. On the basis of these data, in 1992, the National Surgical Adjuvant Breast and Bowel Project (NSABP) began a randomized, placebo-controlled study (P-1 trial) to test the efficacy of 5 years of tamoxifen in the prevention of breast cancer. Between 1992 and 1997, 13,388 women with a 1.% or greater predicted risk of developing breast cancer within 5 years were enrolled in this trial. Risk was assessed with a modification of the Gail model that allowed enrollment of any woman older than 60 years and of selected women younger than 60 years with additional risk factors that increased their annual risk to at least that of a 60-year-old woman. Women with a history of LCIS were also included because their risk was thought to exceed the cutoff risk of 1.67%. Women were not allowed to use estrogen replacement therapy during their participation in the trial.The results of the P-1 trial indicated that tamoxifen reduced the rates of invasive and noninvasive breast cancer by 49% and 50%, respectively. The benefit of tamoxifen was seen in all age groups (≤49 years, 50 to 59 years, and ≥ 60 years). Women with a history of atypical ductal hyperplasia had an 86% risk reduction, and women with a history of LCIS had a 56% risk reduction. The benefit was seen across all subgroups specified according to family history of breast cancer. Tamoxifen selectively reduced the incidence of estrogen receptor–positive tumors; estrogen receptor–negative tumors developed at an equal rate in the tamoxifen and placebo groups. No evidence of a cardioprotective effect of tamoxifen was found in this trial, but the number of osteoporosis-related fractures was reduced in the tamoxifen-treated cohort. Tamoxifen increased the risk of developing stage I endometrial cancer (risk ratio=2.53).Although this study indicated that 5 years of tamoxifen use decreased the 5-year risk of developing breast cancer by about 50%, whether this result warrants the widespread use of tamoxifen for breast cancer prevention is controversial. In the NSABP report, 5 years of tamoxifen therapy for 6576 women reduced the number of invasive or noninvasive breast cancer by 120 compared with the expected number. Because the follow-up period of this important study was relatively short, however, it was not possible to determine whether tamoxifen prevented this number of cases of breast cancer or instead delayed the onset of the disease.

 

Raloxifene and Other Newer Agents

After completion of the P-1 study, the NSABP began a prospective, randomized prevention trial comparing tamoxifen and raloxifene, a drug originally approved for treatment of osteoporosis that was coincidentally found to be associated with a lower risk of breast cancer development. The Study of Tamoxifen and Raloxifene (STAR or P-2 trial), enrolled 19,474 postmenopausal women and randomly assigned them to receive 5 years of either drug. The initial results of this study indicated no differences in the rate of invasive breast cancer development between the two drugs. Tamoxifen was associated with higher risks of developing endometrial cancer and deep venous thrombosis. The number of DCIS cases was higher in the raloxifene group (80 cases) than in the tamoxifen group (57 cases). Based on the equivalence in breast cancer prevention and the more favorable side effect profile, the NSABP elected to pursue raloxifene as the new standard breast cancer preventive agent for subsequent clinical trials.The positive findings of the P-1 and P-2 trials proved that pharmacologic manipulation of estrogen signaling could effectively prevent breast cancer. In the near future, a host of more selective means of modifying breast cancer development risk is expected to be tested and approved. Preliminary findings from therapeutic trials of breast cancer have indicated that aromatase inhibitors also have significant chemopreventive activity, and some of these agents will be formally compared with raloxifene in the subsequent NSABP chemoprevention study.

 

Prophylactic Surgery

An alternative strategy used to prevent breast cancer development is prophylactic surgery. Hartmann and colleagues analyzed outcomes in women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at Mayo Clinic between 1960 and 1993. At a median follow-up time of 14 years, only 4 of the 639 treated patients had developed breast cancer. According to the Gail model, 37.4 cases of breast cancer would have been expected to develop in this population, so the prophylactic surgery resulted in an 89.5% risk reduction (P < .001). Prophylactic mastectomy has also proved to be an effective risk reduction strategy for women with a germline mutation in BRCA1 or BRCA2. In a study of 483 BRCA carriers, the breast cancer development rate was only 1.9% in the 105 women who underwent prophylactic mastectomy compared with 48.7% in those who did not.82 For BRCA carriers, prophylactic oophorectomy also can reduce the risk of breast cancer development. In one study, Rebbeck and colleagues83 reported that the rate of breast cancer among 99 BRCAcarriers who had undergone oophorectomy but not mastectomy was 21%; the comparable rate among 60 matched controls was 42%.