Why Women Still Die From Breast Cancer

Shahla Masood, M.D., FCAP, MIAC
Shahla Masood, M.D., FCAP, MIAC is Professor and Associate Chair,
Department of Pathology University of Florida Health Science Center / Jacksonville
and Chief of Pathology and Laboratory Medicine, University Medical Center.

Breast cancer is a heterogeneous disease with a rather unpredictable outcome and is the second leading cause of cancer death among women in the United States. Over 150,000 women are diagnosed with breast cancer each year and 45,000 women die of this disease every year in the United States alone.

Breast cancer is a serious illness affecting not only the physical, but also the emotional well being of many women around the world and is associated with significant psychiatric morbidity. Initially, feelings of shock, devastation, disappointment, failure, guilt and/or anger are the most common presentations. Later, denial is followed by acceptance, but ultimately a certain percentage of patients experience varying degrees of anxiety and depression. Similar reactions have also been observed in recurrent breast cancer. Many variables can influence the degree of psychiatric morbidity in patients with breast cancer, among which the family support and understanding of the disease process play a major role.

The incidence of breast cancer in developed countries is 200 to 250 per 100,000 women per year. Moreover, the incidence increases with age. Other factors with relative risk at least four times that of the general population are personal history of prior breast cancer, family history of bilateral, pre-menopausal or familial cancer syndrome and atypical proliferative breast disease, especially with family history. Moderately elevated risk, i.e., relative risk two to four times that of the general population, includes any first degree relative with history of breast cancer, upper social/economic class, prolonged uninterrupted menses, postmenopausal obesity, personal history of prior carcinoma of ovary or endometrium and proliferative breast disease with no atypia. Patients with history of menarche <12 years of age and moderate alcohol intake may have slightly increased risk, i.e., one to two times that of the general population. The relationship between hormonal replacement therapy, use of oral contraceptives, as well as diet and breast cancer is still under investigation.

Only 25% of women who get breast cancer have known risk factors. Hereditary breast cancer accounts for only 5% of the cases. Genesis may be multifactorial, with genetic, inherent metabolic and environmental components. A variety of oncogenes, tumor suppressor genes and growth factors have been identified that may play a role in the initiation of the breast cancer and its progression to a metastatic stage. A breast cancer susceptibility gene, BRCA1, has recently been discovered. It is localized to the chromosomal region 17q12-q21 on the long arm of chromosome 17. Shortly after this discovery, researchers announced the discovery of a second familial breast cancer gene BRCA2 on the short arm of chromosome 13. BRCA1 is also responsible for a large proportion (more than 75%) of inherited predisposition to ovarian cancer. The second susceptibility gene for breast cancer, BRCA2, is found in about one-third of cases of familial breast cancer.

The identification of susceptibility genes in high risk families can assist in risk estimation for genetic counseling and serve as a guide in choosing candidates for clinical trials of breast cancer screening and chemoprevention. However, the medical, ethical, psychological and legal implications of genetic susceptibility testing on the unaffected "carrier" of a mutated gene are major issues of concern. These issues need to be addressed in detail by researchers and clinicians before genetic susceptibility testing can be used to guide management strategies for high risk breast cancer patients. In addition, there is not yet sufficient insight into environmental causes for breast cancer to suggest lifestyle changes that might lead to the prevention of breast cancer. Another challenging issue is the role of prophylactic mastectomy in patients with inherited risk factors for breast cancer. Although some guidelines have been suggested by the Society of Surgical Oncology for selection of patients to receive prophylactic mastectomy, to date there is no compelling statistical or epidemiological data and no uniform absolute indications for it. The decision to undergo this type of procedure must be made by the woman after careful consideration of other individual risks, breast size and how difficult her breasts are to be examined by mammography and physical examination. The psychological impact of this decision should also be carefully evaluated since the psychological morbidity of prophylactic mastectomy rivals that of mastectomy for carcinoma.

Over the past few decades, substantial progress has been made in the diagnosis and treatment of breast cancer. Advances in breast imaging and emphasis on screening programs have led to the increased detection of in situ lesions and small breast carcinomas. Minimally invasive and cost effective diagnostic sampling procedures such as fine needle aspiration and core biopsies have almost replaced open surgical biopsies. Breast conservation therapy and reconstructive surgery have enhanced cosmetic results with a positive impact on the sexuality and self-image of breast cancer patients.

Sentinel node biopsy has provided an improved alternative to the traditional axillary node dissection. The expanded role of radiotherapeutics and widespread utilization of adjuvant or neoadjuvant chemotherapy have contributed to improved patient outcome. In addition, advances in molecular biology testing and recognition of predictive/prognostic factors have provided new opportunities for novel, effective and individualized cancer therapy.

Furthermore, recent discovery of breast cancer genes and the dramatic efforts to identify risk factors may ultimately lead to the detection of precursor lesions and the prevention of breast cancer. More importantly, the enhanced public awareness of breast cancer has resulted in increased funding for biomedical research, behavioral science, education, research, screening, treatment and survivorship.

Despite this progress, the rate of decline in breast cancer mortality in the last 20 years has not been significant and the question of "why women die from breast cancer" remains unanswered. Various factors contribute to the complexity of breast cancer issues. These include our limited understanding of the biology and natural history of breast cancer, variability in diagnostic criteria, significant diversity in management and therapy and lack of universal acceptability of screening procedures and follow-up therapy.

Breast cancer is one of the most poorly understood malignancies. Prospective studies focusing on the natural history of precursor lesions are limited. Early detection of precursor lesions is, however, the key to the reduction of mortality from breast cancer. This involves understanding of the genetic events, the metabolic alterations and the morphologic changes which occur during the neoplastic progression. It is essential to find ways to detect these changes before a lesion becomes malignant.

The major challenges involved in this discovery process include difficulty in the detection of precursor lesions by mammography alone and the inherent differences in clinical and radiologic presentations among precursor lesions, i.e., lobular carcinomas in situ versus ductal carcinoma in situ. Similarly, morphologic distinction between atypical ductal hyperplasia and low grade ductal carcinoma in situ has remains an unresolved problem.

The confusion surrounding the reproducibility of the current diagnostic criteria among pathologists is a serious problem and often leads to under treatment or over treatment. Apparently, none of the histologic criteria can reliably distinguish between the two entities. Interestingly, aside from similar morphologic features, atypical ductal hyperplasia and low grade ductal carcinoma in situ share similar biological markers.

Considering the facts, it may be advisable to consider these two entities as a single disease, design long term prospective studies and monitor the course of these entities radiologically, biologically and morphologically. This may be the only way that we will ultimately resolve the continued dilemma of interobserver variability in the distinction between atypical ductal hyperplasia and low grade ductal carcinoma in situ.

It appears that the time has come to depart from casual observations and move towards scientific evidence which has been challenged by time. Recent advances in molecular biology and digital and functional imaging, coupled with the ability of fine needle aspiration biopsy to provide tissue samples for monitoring progression of the neoplastic process provide a unique opportunity to better understand the biology of precursor lesions.

Identification of clinically occult high risk proliferative breast disease and premalignant lesions by cytology via aspiration biopsy and nipple secretion may serve as the future pap smear for breast cancer. This is a concept that may no longer be considered a fantasy. Since the introduction of pap smear, the mortality from cervical cancer has reduced by 70% across the globe. Similar reduction may occur if we direct our attention to non-traditional ways of early detection and breast cancer prevention. This naturally requires fostering of adequate funding for biomedical research. The government, state legislators, community leaders and the public should be effectively educated to understand the ultimate life saving and cost-saving effects of research.

It should also be recognized that "breast cancer" is a "subspecialty within a multidisciplinary team." Any member of this team or the "breast physician" must be familiar with the heterogeneity of breast cancer; the role of chemotherapy, radiation therapy and conservative surgery; the fundamental concept of biological markers; the value of reconstructive surgery and high dose chemotherapy; bone marrow transplantation or autologous stem cell support. In addition, the breast physician should be a good listener, a psychiatrist, and a good friend to the patient and her family. The fear is that as the invasion of managed care expands, accessibility to these services will be more limited, particularly for the lower socioeconomic population. Thus, the responsible physician should conscientiously undertake all the necessary measures to assure the well being of all women with breast cancer.

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January, 1999/ Jacksonville Medicine

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