Breast cancer, accounting for 25% of all cancers, remains the second most common cause of cancer worldwide, with an estimated 1.67 million new cancer cases diagnosed in 2012.¹ It is by far the most common cancer in women, both in more and less economically developed regions, with slightly more cases in less developed (883,000 cases) than in more developed (794,000) regions.¹

Incidence rates vary nearly fourfold across the world regions, with rates ranging from 27 per 100,000 in Middle Africa and Eastern Asia to 96 in Western Europe.¹ The higher incidence of breast cancer in women in Western Europe and the United States is possibly associated with higher median population age, robust early detection programs, better control of other causes of early life mortality, and recent increases in obesity. It has been suggested that inflammation could play a role in the pathogenesis of breast and other cancers in obese and overweight patients.²,³,⁴ The rising breast cancer incidence in women of developing nations has also been attributed to “westernized” lifestyle changes including dietary changes, decreased exercise, and reproductive changes such as delayed childbearing, lower parity, and reduced breast-feeding.⁵,⁶

Breast cancer incidence has, however, declined in developed countries since 2003 and is associated with the marked decrease in the use of HRT among postmenopausal women following publication of the Women Health Initiative report that showed an increased breast cancer risk of about 10% for every 5 years of HRT use and even greater risk with combined estrogen/progesterone products than with estrogen therapy alone.⁷ Since 2004, overall breast cancer incidence rates have remained relatively stable.⁸

Breast cancer is less lethal than many other solid tumors and ranks as the fifth cause of death from cancer overall (522,000 deaths). It is, however, the most frequent cause of cancer death in women in less developed regions (324,000 deaths, 14.3% of total) but the second cause of cancer death in more developed regions (198,000 deaths, 15.4%) after lung cancer.¹ The range in mortality rates between world regions is less than that for incidence because of the more favorable survival of breast cancer in (high incidence) developed regions, with rates ranging from 6 per 100,000 in Eastern Asia to 20 per 100,000 in Western Africa.¹ Currently, more women survive because of earlier diagnosis and
better therapy,⁹ and the absolute number of deaths per year has been declining since about 1990 with a disease-specific mortality decrease of 2.2%/year since then, with a more prominent decline noted in women younger than 50 years (3.1%/year) than women 50 and older (1.9%/year).⁸

The incidence of breast cancer varies among different racial groups and ethnicities. Caucasian women in the United States are more likely to develop breast cancer compared with African American women for most age groups; however, African American women have a higher incidence rate before age 40 and are more likely to die from breast cancer at every age.¹⁰

This is confounded, however, by the general increase in cancer-related mortality for lower socioeconomic groups regardless of specific ethnicity.

Although discrete causes of breast cancer cannot be identified in most individual women, many factors increase a woman’s risk of developing the disease. Among the strongest of the risk factors is family history, particularly if more than one family member has developed breast cancer at an early age.¹¹

More precisely, genetic linkage analysis led to the discovery of dominant germ-line mutations in two tumor-suppressor genes, BRCA1 and BRCA2, localized to chromosomes 17 and 13, respectively, which are associated with a high risk of female breast cancer as well as ovarian cancer (BRCA1 and BRCA2), male breast cancer (BRCA2), and other cancers.¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷ Although these mutations account for less than 10% of all cases of breast cancer, together they account for about 45% of families with multiple cases of breast cancer and up to 90% of families with both breast and ovarian cancer.¹⁸,¹⁹ These mutations are present in less than 1% of the general population, but occur more often in certain ethnic groups such as those of Ashkenazi (Eastern European) Jewish descent.¹⁸ However, if a woman with breast cancer is below the age of 50 years and has any relative who developed breast cancer before she was 50 years old, her chance of having a mutation in BRCA1 or BRCA2 rises to as much as 25%.¹⁹ Other factors that increase her probability of a mutation include any relative with ovarian cancer or a personal history of bilateral breast cancer or ovarian cancer. Carriers of these mutations have up to a 70% lifetime risk of breast cancer, depending on familial history, perhaps the specific mutation, and other cellular genes that may modify penetrance.¹⁷ The 5-year survival rate of patients with either of the BRCA mutations is not significantly less than for other patients with breast cancer after adjusting for the specific subtypes of breast cancer carriers tend to develop.

It is important to note that most patients with a family history of breast cancer do not have a defined inherited mutation and other, less common, causative mutations are sometimes seen.¹⁹,²⁰ Rarer inherited conditions associated with increased breast cancer
risk include Li-Fraumeni (germ-line mutations in p53) and Cowden syndromes (80% due to mutations in PTEN) and a number of more common genetic mutations. PALB2 (partner and localizer of BRCA2) has been previously identified as a moderate-risk gene in breast cancer and germ-line loss-of-function PALB2 mutation carriers have a lifetime risk of breast cancer as high as the risk borne by BRCA2 mutation carriers.²¹,²²

Beyond molecular testing for BRCA1/2, multiplex test panels are now commercially available, identifying both high- and moderate-penetrance genes for use in families who test negative for known familial cancer syndromes. However, a limited understanding of the risk associated with moderate-penetrance genes and the potential for detection of variants of uncertain clinical significance (VUCS) complicate the interpretation of test results. Comprehensive genetic counseling should be done prior to testing, to ensure test results appropriately modify the clinical care of these patients.²³,²⁴

Additional factors that increase breast cancer risk are early menarche, late menopause, nulliparity, late age at birth of first child, and prior benign breast disease (particularly if there is a high degree of benign epithelial atypia).²⁵,²⁶ Although breast cancer may occur among men, such cases represent less than 1% of all breast cancers. Male carriers of BRCA2 mutations have a 6% lifetime risk of breast cancer, significantly increasing their risk in comparison with the general population.

The risk of hormone receptor-positive breast cancer can be reduced. At least three trials using selective estrogen receptor modulators (SERMs) have demonstrated that 3 to 5 years of preventive treatment with these agents reduces the rate of breast cancer development over the short term.²⁷,²⁸,²⁹,³⁰ Women at increased risk because of family history, age, and other risk factors, who are treated with the SERM tamoxifen, 20 mg/day, were found to have a 45% reduction in the rate of occurrence of invasive breast cancer compared with women treated with placebo. Noninvasive disease and preneoplastic breast lesions were also decreased. Raloxifene, 60 or 120 mg/day, also appears to reduce the risk of breast cancer in postmenopausal women (who had osteoporosis and a standard or reduced risk of breast cancer), with a relative risk of 0.26.³¹ Despite these benefits, SERMs are associated with an increased risk of both venous thromboembolism and endometrial cancer, although the risks with raloxifene appear to be lower than tamoxifen, which has been associated with an increased risk for endometrial cancer of 1.5 to 2 times that of untreated women.²⁷ In addition, neither of these agents have demonstrated an improvement in survival when used for breast cancer prevention. In the Study of Tamoxifen against Raloxifene trial, these agents were compared and although there were
no significant mortality differences, raloxifene was found to have 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer and less thromboembolic events).³² A meta-analysis of all nine prevention trials with tamoxifen, raloxifene, arzoxifene, and lasofoxifene showed an overall 38% reduction in breast cancer incidence.³³ Indeed after 20 years of follow-up, the long-term benefits of 5 years of tamoxifen remain with a number needed to treat (NNT) of 22 to prevent one breast cancer (95% CI, 19 to 26).³⁴ These agents have similar but not identical toxicity profiles that may guide clinical decisions.

Aromatase inhibitors (AIs) have also been shown to be beneficial as prevention in the postmenopausal population at high risk. Five years of exemestane significantly reduced the incidence of invasive breast cancers by 65% with only minimal changes in health-related quality of life and without serious toxic effects.³⁵ Similarly, anastrozole was shown to reduce the risk of developing hormone receptor-positive invasive breast cancer and preinvasive cancers by 50%.³⁶

There are several options in the management of women at very high risk because of family history or known gene mutations. Increased surveillance, through the addition of magnetic resonance imaging (MRI) screening on a yearly basis as a supplement to standard mammography, was effective in a high-risk population. In mutation carriers who are at risk for both breast and ovarian cancer, bilateral oophorectomy after childbearing age (before age 50 years but possibly as early as 35) has been recommended because of the inadequacy of screening tests for ovarian cancer and because it reduces the risk of both primary breast cancer by approximately 50% and the risk of ovarian cancer by approximately 80% and is associated with a lower all-cause mortality.³⁷,³⁸,³⁹ Risk-reducing mastectomy is an effective option with a relative risk reduction of about 90%.³⁷,⁴⁰ Note that despite risk-reducing mastectomy, there is always a small risk of breast cancer in residual breast glandular tissue. SERMs may be useful in patients with BRCA1 and BRCA2 mutations as well. Analysis of blood samples of women who participated in the P-01 (tamoxifen) trial showed that mutation carriers also had a 47% lower risk of breast cancer.⁴¹,⁴² Tamoxifen has also been shown to reduce contralateral breast cancer incidence in this high-risk population.⁴³

Because more lives can be saved if breast cancer is diagnosed at an early stage, many screening programs have been designed to detect small, early cancers. Monthly breast self-examination for all women after puberty and yearly breast examinations by a
physician or other trained professional after a woman is 20 years of age is generally recommended, although evidence of effectiveness is limited. Mammography reduces breast cancer mortality by 25% to 30% in women older than 50 years.⁴⁴ The benefit for women aged 40 to 50 years has been more difficult to demonstrate because the incidence of breast cancer is lower.⁴⁵,⁴⁶ Hence, more examinations are needed to find a cancer and save a life. However, additional benefits of early detection via mammography include the option for less disfiguring surgery, reduced utilization of radiation therapy, and decreased need for chemotherapy and other systemic treatments. Therefore, the absolute benefits extend beyond the simple end point of survival. As a result, mammography is recommended at age 40 years as a baseline, once every 1 to 2 years between the ages of 40 and 50 years (depending on risk factors and the recommending organization), and yearly after 50 years of age. An upper age of effectiveness is not established. For high-risk women and in family members of mutation-positive patients, annual mammography should be initiated 10 years earlier than the youngest diagnosed relative. Patients with Hodgkin lymphoma (regardless of a history of mantle field irradiation) should have a baseline mammogram by age 25. In BRCA1/BRCA2 mutation carriers, beginning at age 25, annual MRI of the breast in addition to annual mammography is recommended as its use has detected more interval and earlier stage cancers and has reduced the incidence of large or lymph node-positive breast cancers.⁴⁷,⁴⁸ Mammography has clearly led to the discovery of many earlier cancers and sharply increased the discovery of preinvasive cancers (ductal carcinoma in situ [DCIS]). These latter are not (yet) invasive and their treatment can be far less complicated than that of invasive breast cancer. Other screening modalities can include ultrasound, but it is more typically used diagnostically to evaluate palpable lesions.

Although a large number of nonpalpable cancers are found by mammography, invasive breast cancer is still often discovered by a woman herself as an isolated, painless lump in the breast. If the mass has gone unnoticed, ignored, or neglected for a time (or if it is particularly rapidly growing or aggressive), there may be fixation to the skin or underlying chest wall, ulceration, pain, or inflammation. Some early lesions present with discharge or bleeding from the nipple. Occasionally, the primary lesion is not discovered, and the woman presents with symptoms of metastatic disease, such as pleural effusion, nodal disease, or bony metastases. About half of all lesions are in the upper outer quadrant of the breast (where most of the glandular tissue of the breast is). About 20% are central masses and 10% are in each of the other quadrants. Up to one-quarter of all women with breast
cancer have axillary node metastasis at the time of diagnosis, although this is less common when the primary tumor has been detected by screening.

3. Staging. Carcinoma of the breast is staged according to the size and characteristics of the primary tumor (T), the involvement of regional lymph nodes (N), and the presence of metastatic disease (M). The TNM classification of breast cancer and stage grouping are used, which is published by the American Joint Commission on Cancer.⁴⁹ Although preliminary staging is commonly done before surgery, definitive staging that can be used for prognostic and further treatment planning purposes usually must await postsurgical pathologic evaluation when the primary tumor size and the histologic involvement of the lymph nodes are established. In up to 30% of patients with palpable breast masses (not found by mammography) but without clinical evidence of axillary lymph node involvement, the histologic evaluation of the nodes reveals cancer. In patients with negative nodes by routine histologic evaluation, serial sectioning may reveal microscopic cancer deposits in additional patients. The principal changes in the new staging system take into consideration the widespread use of immunohistochemical (IHC) and molecular biologic techniques that afford pathologists the ability to detect microscopic metastatic lesions down to the level of isolated tumor cells. It is not clear that there is prognostic value if cancer cells in nodes are detected by enhanced examination, and the current staging system designates nodes as pathologically negative if cells are identified by IHC alone and are in clusters of less than 0.2 mm. The identifier “(i)” is used to indicate isolated tumor cells such that pN0 (i+) indicates node-negative disease but the presence of such cells in the node. Similarly, “(mol +)” indicates that a molecular examination such as polymerase chain reaction has found evidence of malignant cells.

1. Before biopsy the woman should have a careful history, during which attention should be paid to risk factors, and a physical examination, with a focus not only on the involved breast but also on the opposite breast, all regional lymph node areas, the lungs, bone, and liver. This examination should be followed by bilateral mammography to help assess the extent of involvement and to look for additional ipsilateral or contralateral disease.

2. Excisional or core needle biopsy of the primary lesion is performed, and the specimen is given intact (not in formalin) to the pathologist, who can divide the specimen for histologic examination, hormone receptor assays, and HER2 testing (by immunohistochemistry examination or fluorescence in situ hybridization [FISH]).

3. After confirmation of the histology, the patient is evaluated for possible metastatic disease. It is important to emphasize that
history and physical examination are the most critical components of this assessment.

a. Typical studies include a complete blood count, and blood chemistry profile.

b. Other studies that may be considered based on symptoms or signs or abnormal blood work, include radionuclide scan of the bones, skeletal survey (usually obtained only if the radionuclide scan is positive), and computed tomography (CT) scan of the liver (abdomen) and chest. PET CT is another option that may be helpful in the evaluation of locoregional disease.

About 75% to 90% of all breast cancers are infiltrating ductal carcinomas, and up to 10% are infiltrating lobular carcinomas; these two types have similar overall behavior but the latter tend to be hormone responsive and HER2-negative. In addition, their patterns of metastatic spread can vary even if the overall risks of metastases are similar. The remainder of the histologic types of invasive breast carcinoma may have a somewhat better prognosis but are usually managed more according to the stage than to the histologic type. Microarray technology has added nuance to the traditional, histology-based categorization of breast cancer and supports the view that this is a disease with distinct subtypes. About 15% of breast cancers are basal-like (basal epithelial subtype), with a relatively high concordance with the conventionally defined “triple negative” (hormone-receptor and HER2-negative) subset.⁵⁰ Luminal tumors are generally hormone receptor-positive, but it is the luminal A subtype that is most clearly hormone responsive, and the luminal B subtype is clinically distinguished by either expression of HER2 or high proliferation rates.⁵¹

Basal-like tumors are seen in association with BRCA1 mutations and are more common in African American women.⁵² Each of these subtypes (luminal A, B, basal-like, HER2-positive, etc.) is associated with a distinct typical natural history in terms of time to develop distant metastases.⁵³

Many institutions have established multidisciplinary teams or centers to facilitate coordinated treatment planning. It may be useful in some settings to pursue this particular clinical care structure, but there are other reasonable strategies to employ in the development of an optimal care plan for individual patients.

1. Consultation with a surgeon, radiotherapist, and medical oncologist is generally required once the diagnosis of carcinoma is suspected or histologically confirmed or after definitive surgery has been accomplished. Multimodal therapy has had a profound impact on the outcome of breast cancer as it has allowed for organ preservation and improved disease-free survival (DFS) and
overall survival. Any clinician treating patients for breast cancer should be very familiar with the roles and interventions offered by the other members of the team. It is also critical to have the patient (and her family if she desires) share in the therapy decisions after hearing the options, the relative advantages and disadvantages of each approach, and the recommendations of the consultants. The patient should be given an opportunity to hear why the recommended treatment is thought by the physicians to be best and to decide whether the treatment is appropriate for her.

2. Goals of therapy differ depending on the stage of disease being treated.

3. For early-stage invasive disease, the goal of therapy is to eradicate the primary tumor and to suppress the growth of or eliminate micrometastases, thereby preventing recurrence and death. In the postoperative setting, this is called adjuvant therapy. There are three broad classes of systemic adjuvant therapy: hormone therapy (tamoxifen or, in postmenopausal women, an aromatase inhibitor), chemotherapy (any of a large number of standard combination regimens), and HER2-directed therapy (trastuzumab +/- pertuzumab for patients with HER2-positive tumors). These options are weighed and combined on an individualized basis based on careful risk-benefit analyses. Of course, while treating postoperative patients who may be cured by their surgery (and radiation therapy), we seek to avoid unnecessary short- and long-term drug-induced toxicities. Of particular concern is the increased incidence of second cancers (myelodysplasia and leukemias in particular with chemotherapy, and uterine cancer with tamoxifen) arising years after the completion of therapy. Other risks can include osteoporosis with AIs and cardiac dysfunction following anthracycline or trastuzumab use. It is important to emphasize that despite these toxicities, overall survival has generally been improved in the patient populations treated with these modalities.⁵⁴ However, one goal of ongoing investigational studies is to determine the minimum therapy that is effective for preventing the maximum number of recurrences in any given clinical situation.

4. For locally advanced disease defined as stage IIIA or T3-T4 disease or more, including inflammatory breast cancer, the goal of systemic therapy changes somewhat. In addition to critically important systemic control, there is the added potential benefit of local response facilitating less disfiguring surgery and, in some cases, any surgery. This is referred to as neoadjuvant or preoperative systemic therapy, and it specifically can reduce the size of an initially unresectable tumor or convert the planned surgical intervention from mastectomy to breast conservation. In the research setting, preoperative administration of systemic
therapy allows the opportunity to test both the therapeutic efficacy of novel drugs and regimens as well as the ability to conduct correlative science studies, thereby potentially optimizing drug development.

5. For advanced (metastatic) disease the goal of therapy is to lengthen survival when possible and to palliate or limit symptoms and signs of the disease using therapy with an acceptable toxicity profile. In this setting, long-term toxicity is not usually of great importance, but short-term toxicity is a major focus for both physician and patient because the aim of therapy is to improve how the patient feels (quality of life) as well as to prolong survival. The general approach is to use hormone therapy if possible, anti-HER2 therapies when HER2 is amplified or overexpressed in the tumor, and chemotherapy as sequential single agents. There are a myriad of novel targeted therapies in development and an increasing number of treatments with proven impact on overall survival.

6. Surgery remains the most frequently used mode of primary therapy for the vast majority of women with breast cancer. Over the past half century, the extent of surgery has evolved toward less disfiguring procedures. Hence, breast conservation (lumpectomy) with radiation therapy and an examination of the sentinel nodes (or in some cases, an axillary node dissection) is now routine. Surgical margins should be free of tumor, but an exact definition of the safe width is not uniformly accepted. Complete axillary node dissection is unnecessary in most cases when a sentinel node procedure, performed by an experienced surgeon, reveals no cancer.⁵⁵ Following breast conservation (and generally after the completion of chemotherapy), radiotherapy is delivered to control any microscopic cancer remaining in the breast. The decision to radiate nodal fields varies with the stage of the cancer. In terms of distant DFS and overall survival, appropriate candidates for breast conservation have the same outcomes as if they were treated with mastectomy.⁵⁶ Therefore, many patients opt for breast-conserving surgery and radiotherapy over mastectomy. Apart from patient preference, mastectomy is indicated when the tumor is too large or locally advanced to allow breast conservation (although preoperative systemic therapy can facilitate breast conservation in this situation), if the tumor is multicentric/multifocal, when the patient has a contraindication to radiation therapy, if it is an ipsilateral recurrence in a previously radiated breast (again, a contraindication to additional radiation therapy), or when margins free of tumor cannot be obtained.

There remain wide geographic variations in the use of breast-conserving surgery throughout the United States and without obvious medical justification. For patients who have had mastectomy, reconstruction can be accomplished by several
approaches and requires a skilled plastic surgeon. It may be done at the time of mastectomy or delayed for a period (usually 1 to 2 years). There is no evidence that any (or no) reconstructive approach has any impact on the natural history of breast cancer.⁵⁷

7. Radiation therapy. The role of radiation therapy in the management of carcinoma of the breast has been expanded since the early 1970s. Radiotherapy is now commonly used in conjunction with breast conservation as part of the primary therapy. In this circumstance, the radiotherapy is commonly delivered to the entire breast with a boost of therapy to the tumor bed using external-beam therapy. More recently, shorter courses of external-beam radiation may be considered for treating the breast only.⁵⁸ In addition, radiation therapy to only the affected part of the breast is now used in early-stage disease. Partial breast irradiation may be delivered by brachytherapy or focused external-beam treatment. Radiotherapy may also be employed following mastectomy in women who have a particularly high likelihood of local recurrence. When the risk of local recurrence is high, radiation therapy is associated with improved overall survival.⁵⁹ Typically, postmastectomy radiation is indicated if the primary tumor is larger than 5 cm or if four or more positive lymph nodes were found in the axilla, although there is potential benefit on survival even in lower risk patients, such as those with one to three positive axillary lymph nodes.⁵⁹ Following breast conservation, radiation may be omitted in patients older than 70 years of age with estrogen receptor-positive tumors smaller than 2 cm if they are treated with antiestrogen therapy.⁶⁰ However, with longer follow-up, an increase in breast recurrences is found without radiation, but with no detectable impact on survival.⁶⁰ Radiation therapy is generally administered after completion of cytotoxic therapy (when indicated). Radiation therapy is also helpful as adjunctive therapy for metastatic or locally advanced and unresectable disease. Local recurrences and isolated or specific (e.g., painful bone lesions particularly with impending fracture) distant metastases also are frequently treated successfully with radiotherapy.

8. Systemic therapy is used to reduce the likelihood of recurrence after local therapy for early-stage disease and to treat more advanced disease with or without distant metastasis. For operable (curable) breast cancer, The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) analysis of adjuvant therapy demonstrates a clear benefit of postoperative chemotherapy or hormonal therapy (including ovarian ablation in premenopausal women).⁵⁴ Although the precise estimates of benefit vary with each half-decade review and update, in very general terms systemic therapy reduces the risk of recurrence by as much as 50%. Similarly, the odds of death are also reduced by as much as 30%.
Similar proportional risk reductions are seen in node-positive as well as node-negative disease with the proviso that lower risk disease yields proportionately smaller absolute benefits for therapy.⁶¹ Historically, medical oncologists relied on node status, tumor size and grade, hormone receptor status, HER2 status, and perhaps DNA synthesis rate (percentage of cells in the synthesis phase), as well as any of a number of other factors to aid in determining risk for individual patients so that the oncologists could then estimate the benefits of specific systemic therapies and guide patients. More recently, commercially available tests (genomic assays) that provide prognosis, or more importantly, prediction of benefit for specific systemic therapies, have become available.⁶²,⁶³ As always, physiologic age of the patient and comorbid conditions are also important considerations in adjuvant therapy decisions.

9. Endocrine therapy includes surgical, radiotherapeutic, or drug-induced ablation or inhibition of ovarian function. It also includes antiestrogens (typically SERMs), AIs, progestins, androgens, and even corticosteroids. Tumors with no expression of either the estrogen or the progesterone receptor will generally not respond to hormone therapies, and the greater the expression of these receptors the greater the probability of benefit.⁶⁴ However, there is no clear threshold (above zero) below which one can be certain that endocrine therapy will be ineffective.⁶⁵ Similarly, when the estrogen receptor is detected, it is not clear that the level of the progesterone receptor is important. Variations in test quality and results remain important challenges in this area.

Breast cancer can vary from aggressive and rapidly fatal to relatively indolent disease with late-appearing metastasis. Molecular studies increasingly support the view that breast cancer is a collection of diseases rather than one single entity. At present, clinicians can use the following factors to provide crude estimates of the likelihood of relapse and survival, but this is an area where newer diagnostics may rapidly improve our current approach.

1. Stage. Axillary node involvement and the size of the primary tumor are major determinants of the likelihood of survival.⁶⁶,⁶⁷,⁶⁸

a. Nodes. In the first National Surgical Adjuvant Breast and Bowel Project (NSABP) study, before the use of modern adjuvant therapy, 65% of all patients who underwent radical mastectomy survived 5 years, and 45% survived 10 years.⁶⁹ When no axillary nodes were positive, the 5-year survival rate was nearly 80% and the 10-year survival rate 65%. If any axillary nodes were positive, the 5-year survival rate was less than 50% and the 10-year survival rate 25%. If four or more nodes were positive, the 5-year survival rate was 30% and the 10-year survival rate less than 15%.

Since that time (1975), there has been an improvement, with 5-year survival rates of 99% for stages I and II, 85% for stage III, and 25% for stage IV breast cancer.⁷⁰ Lymph node involvement by conventional light microscopy remains the single most important prognostic factor in making survival predictions and treatment decisions. It is important to distinguish modern cases in which malignant cells are detected in lymph nodes using higher sensitivity techniques. Their prognosis is not as clearly established.

Patients with large primary tumors generally face higher risks of relapse and death compared to patients with small tumors, irrespective of the nodal status, although patients with large primary tumors are more likely to have node involvement. Tumors that are fixed to the skin or to the chest wall have worsened prognoses compared to those that are not. Patients with inflammatory carcinomas have a particularly poor prognosis, with a median survival time of less than 2 years and a 5-year survival rate of approximately 30%.⁷¹,⁷² Neoadjuvant systemic therapy has improved the outcome significantly for this subset of patients by enabling local control surgery and improving long-term rates of relapse and death.⁷³,⁷⁴

Although stage of disease is critical in determining the risk of recurrence, the timing of events is heavily influenced by tumor biology, particularly hormone receptor status. Patients with tumors that do not express estrogen or progesterone receptors (or do so at only very low levels) are much more likely to experience recurrence during the first few years after diagnosis than those who have receptor-positive disease.⁷⁵ This observation is true for both premenopausal and postmenopausal patients within each major node group (zero, one to three, and four or more). Over decades, the risk of relapse and death is approximately the same but the distribution of these events is more even with hormone receptor-positive disease and skewed to the earlier years when the receptors are absent.⁷⁵