Nature Medicine4, Special Web Focus: Breast Cancer (2001)
Published online: 16 April 2001; | doi:10.1038/20000257
Recent progress in the understanding and treatment of breast cancer
Leif W. Ellisen & Daniel A. Haber
Breast cancer is the most common cancer among women in the United States, and is second only to lung cancer as a cause of cancer-related deaths. It is estimated that one in eight women will develop breast cancer during her lifetime. Over the past 10 years, the incidence of breast cancer has remained unchanged, although mortality rates have steadily decreased, due to earlier detection and more effective therapy. Risk factors include age (the risk for developing breast cancer by age 40 is 0.5%, compared with 10% by age 80), as well as lifetime exposure to unopposed estrogen (early menarche, late menopause, late first pregnancy or prolonged use of estrogen-based oral contraceptives). Women with certain benign proliferative lesions of the breast, as well as those with a premalignant condition called carcinoma in situ, are also at increased risk for developing invasive breast cancer, and individuals who have already sustained one breast cancer are at increased risk for a second primary tumor.
Germline mutations in the breast cancer genes BRCA1 and BRCA2, present in about 0.1% of the general population, are associated with a high lifetime risk for developing breast cancer at an early age, as is a family history of breast and/or ovarian cancer. Hormonal risk factors are likely to modulate genetic predisposition to breast cancer, although the magnitude of this effect is unknown. Environmental factors, including diet, alcohol intake and obesity, have been suspected but not consistently linked to increased breast cancer risk.
Genetic predisposition Inherited mutations are believed to account for approximately 5% of breast cancer cases, and the number of affected family members and the age at onset are correlated with the penetrance of inherited genetic alterations. Although germline mutations in BRCA1 and BRCA2 contribute to the increased risk of the subset at highest risk, other, possibly less-penetrant genes remain to be discovered. In BRCA1 kindreds, inheritance of a mutant allele also confers predisposition to ovarian cancer; in BRCA2 families, susceptibility to breast cancer is found in both men and women, and may be accompanied by increased risk for ovarian and pancreatic cancer. The genetic or epigenetic factors that modulate these relative risks are not understood. Breast cancer predisposition may also arise in the context of Cowden syndrome (hamartomas, thyroid and breast tumors) associated with germline mutations in the gene for phosphatase and tensin homolog (PTEN) tumor suppressor. Li-Fraumeni syndrome, associated with germline mutations of the gene for tumor protein p53 (TP53) or, in rare cases, RAD53 (formerly known as checkpoint kinase 2, or CHK2), can also cause breast cancer, as well as sarcomas, brain tumors, leukemia and adrenal cancer. With the exception of PTEN, genes that may be involved in predisposition to breast cancer encode proteins that seem to function in the cellular response to DNA damage, emphasizing a salient yet unexplained connection between the maintenance of genomic integrity and organ-specific tumorigenesis.
Invasive ductal carcinoma, low grade. Malignant breast epithelia invade breast stroma as polarized groups of cells that form tubular or duct-like structures.
Molecular alterations in breast cancer The association between certain benign and premalignant lesions of the breast and later malignant disease indicates a stepwise progression of tumorigenesis within breast epithelial cells. However, the somatic genetic events that contribute to breast cancer are only partially understood, and a clear linear progression of events has not been demonstrated in most cases. Overexpression of ERBB2 (HER-2), a member of the human epidermal growth factor receptor family, is found in one-third of tumors, often resulting from amplification of the gene. MYC (formerly known as C-MYC) and CCND (formerly known as cyclin D) are also commonly amplified in breast cancer, whereas the tumor suppressor genes for tumor protein p53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A, formerly known as p16INK4a) and, less commonly, retinoblastoma (RB) are inactivated. Cellular alterations that promote invasion and metastasis may occur at later stages and involve complex tumor-host interactions that are relatively poorly understood.
Paradoxically, mutations in the two main genes for breast cancer predisposition, BRCA1 and BRCA2, are not associated with sporadic breast cancers. Little is known about the genetic differences between breast tumors that arise in germline carriers of these mutations and the more commonly occurring sporadic cancers. The recent application of expression profile analysis, coupled with more sophisticated techniques for isolating and analyzing small numbers of premalignant and malignant cells, should provide a clearer view of the molecular events underlying breast tumorigenesis.
Lobular carcinoma in situ. Malignant breast epithelial cells proliferate within, expand and distend lobular acini. The malignant cells are monotonous and loosely cohesive. The cells do not penetrate the basement membrane and do not infiltrate into the surrounding stroma.
Ductal carinoma in situ, high grade with central necrosis. Malignant breast epithelial cells with enlarged, pleomorphic nuclei proliferate within lobular acini in a nonpolarized pattern (loss of cellular orientation). The cells do not invade the breast stroma.
Screening and chemoprevention The recent decrease in breast cancer mortality has been most clearly linked to improvements in screening and early detection, attributed to heightened public awareness, coupled with improved mammographic technology. The development and testing of more-sensitive screening techniques, such as molecular resonance imaging and potential molecular-based assays, may lead to further progress, especially in younger women whose breast density may preclude adequate screening by conventional mammography, or in those at particularly high risk for developing breast cancer. The availability of genetic testing to identify carriers of BRCA1 or BRCA2 mutations raises essential questions about optimal screening and preventive measures for breast and ovarian cancer, and emphasizes the importance of genetic counseling and maintaining genetic privacy.
Tamoxifen, a selective estrogen response modulator (SERM) that functions as both an estrogen agonist and antagonist, is now used in the chemoprevention of breast cancer. A large US clinical trial reported that tamoxifen reduces the incidence of breast cancer by 50% in women at moderately increased risk. However most breast cancers arising in carriers of mutations in BRCA1 do not express the estrogen receptor, indicating that SERMs may not be effective in this highest risk subset. Tamoxifen has also been associated with increased risk for endometrial cancer as well as blood coagulation abnormalities. Given the large population of women at moderately increased risk for breast cancer, considerable efforts are underway to develop and test improved, tissue-specific SERMs and to assess the relative risks and benefits of prolonged chemopreventive therapy in these otherwise healthy women.
Ductal carcinoma in situ, low grade. Malignant breast epithelial cells proliferate in a cribriform (polarized sieve-like) pattern with lobular acini. The cells that constitute the low-grade in situ carcinoma are more regular in size and shape and demonstrate epithelial polarization as compared with high-ductal carcinoma in situ. These cells do not invade the surrounding stroma.
Treatment of primary and metastatic breast cancer The main trends in the treatment of primary breast cancer over the past two decades have been toward less-extensive surgery and more common use of 'adjuvant therapy'. 'Adjuvant therapy' refers to treatment intended to eliminate presumed microscopic disease and therefore prevent recurrence. From a surgical perspective, mastectomy is now required less commonly, because of the proven efficacy of a more limited 'lumpectomy' combined with local adjuvant radiation therapy. In addition, the biopsy of 'sentinel' draining lymph nodes, identified by injection of a tracer dye, is beginning to replace the traditional extensive surgical dissection of auxiliary lymph nodes to assess lymphatic spread, the most important prognostic indicator for breast cancer. Systemic adjuvant therapy is now recommended for most women after surgical removal of a primary breast cancer. Such treatment may involve chemotherapy and/or hormonal therapy with agents such as tamoxifen, if the primary tumor is shown to express estrogen and progesterone receptors.
Chemotherapeutic drugs and hormone therapy remain the main tools for the systemic treatment of metastatic breast cancer. Approximately two-thirds of breast cancers express the estrogen receptor, with a subset also expressing the progesterone receptor. Disrupting hormone-dependent signaling pathways using tamoxifen or other hormonal agents may have profound initial effects on the survival and proliferation of breast cancer cells, but progressive resistance emerges through mechanisms that are only partially understood. Cytotoxic chemotherapy may also provide temporary disease control; however, the side effects are limiting, and high-dose chemotherapy accompanied by hematopoietic stem cell or bone marrow transplantation has not been proven to be more effective than the lower standard doses.
Investigation into the molecular basis of breast cancer pathogenesis has already provided some clinical benefits in the treatment of metastatic disease. The use of herceptin, a humanized monoclonal antibody directed against the ERBB2 receptor, in combination with chemotherapeutic drugs, improves survival of women whose tumors overexpress this protein. Bisphosphonates, which seem to suppress the osteoclasts involved in bone remodeling, are effective in reducing pain and other complications of bony metastatic disease, and may also have direct anti-tumor activity. Future approaches will involve the development of additional hormonal modulators, new growth factor receptor inhibitors, telomerase inhibitors and a variety of tumor vaccines. Along with improvements in therapeutics, improved molecular characterization of breast cancer may lead to the identification of new tumor cell markers, allowing more-sophisticated classification of breast cancers and improving our ability to predict responsiveness to specific therapy.
Massachusetts General Hospital Cancer Center
and Harvard Medical School
Boston, Massachusetts 02114
