WHAT IS BREAST CANCER?

WHAT RISK FACTORS ARE FOR BREAST CANCER?

PATHOLOGIC FEATURES

Breast cancer is the most common type of cancer among women. In the U.S.,184 200 new cases of invasive breast cancer were diagnosed in 2000.Lifetime risk of developing breast cancer in North American women (who live up to 85 years) is 12.5%.The incidence increases with age, but the rate if increase slows after menopause.

WHAT IS BREAST CANCER?

Breast cancer is a malignant (cancerous) tumor that starts from cells of the breast. The disease occurs mostly in women, but men can get breast cancer as well. The information here refers only to breast cancer in women.

A womanbreast is made up of lobules (glands that make breast milk), ducts (small tubes that connect lobules to the nipple), fatty and connective tissue, blood vessels, and lymph vessels. Most breast cancers begin in the ducts (ductal), some in the lobules (lobular), and the rest in other tissues.

If breast cancer cells reach the underarm lymph nodes and continue to grow, they cause the nodes to swell. Once cancer cells have reached these nodes they are more likely to spread to other organs of the body as well.

WHAT RISK FACTORS ARE FOR BREAST CANCER?

No one knows the exact causes of breast cancer. However, Studies have found the following risk factors for breast cancer:

Age: A woman over age 60 is at greatest risk. This disease is very uncommon before menopause.

Personal history of breast cancer: A woman who has had breast cancer in one breast has an increased risk of getting this disease in her other breast.

Family history: A woman's risk of breast cancer is higher if her mother, sister, or daughter had breast cancer, especially at a young age (before age 40).

Certain breast changes: Having certain types of abnormal cells (atypical hyperplasia or lobular carcinoma in situ [LCIS]) increases the risk of breast cancer.

Genetic alterations: Changes in certain genes (BRCA1, BRCA2, and others) increase the risk of breast cancer.

Reproductive and menstrual history:

• The older a woman is when she has her first child, the greater her chance of breast cancer.
• Women who began menstruation (had their first menstrual period) at an early age (before age 12), went through menopause late (after age 55), or never had children also are at an increased risk.
• Women who take menopausal hormone therapy (either estrogen alone or estrogen plus progestin) for 5 or more years after menopause also appear to have an increased chance of developing breast cancer.

Race: Breast cancer occurs more often in white women than Latina, Asian, or African American women.

Radiation therapy to the chest: Women who had radiation therapy to the chest (including breasts) before age 30 are at an increased risk of breast cancer.

Breast density: Older women who have mostly dense (not fatty) tissue on a mammogram (x-ray of the breast) are at increased risk of breast cancer.

Taking DES (diethylstilbestrol): DES is a synthetic form of estrogen. Women who took DES during pregnancy have a slightly increased risk of breast cancer.

Being obese after menopause: After menopause, obese women will have an increased risk of developing breast cancer. Being obese means that woman has an abnormally high proportion of body fat. Because the body makes some of its estrogen (a hormone) in fatty tissue, obese women are more likely than thin women to have higher levels of estrogen in their bodies. High levels of estrogen may be the reason that obese women have an increased risk of breast cancer. Also, some studies show that gaining weight after menopause increases the risk of breast cancer.

Physical inactivity: Women who are physically inactive throughout life appear to have an increased risk of breast cancer.

Alcoholic beverages: The more alcoholic beverages a woman drinks, the greater her risk of breast cancer.

Clinical breast examination (CBE) seeks to detect breast abnormalities or evaluate patient reports of symptoms to find palpable breast cancers at an earlier stage of progression. Treatment options for earlier-stage cancers are generally more numerous, include less toxic alternatives, and are usually more effective than treatments for later-stage cancers. For average-risk women aged 40 and younger, earlier detection of palpable tumors identified by CBE can lead to earlier therapy. After age 40, when mammography is recommended, CBE is regarded as an adjunct to mammography. Recent debate, however, has questioned the contributions of CBE to the detection of breast cancer in asymptomatic women and particularly to improved survival and reduced mortality rates. Clinicians remain widely divided about the level of evidence supporting CBE and their confidence in the examination. Yet, CBE is practiced extensively in the United States and continues to be recommended by many leading health organizations. It is in this context that this report provides a brief review of evidence for CBE’s role in the earlier detection of breast cancer, highlights current practice issues, and presents recommendations that, when implemented, could contribute to greater standardization of the practice and reporting of CBE. These recommendations may also lead to improved evidence of the nature and extent of CBE’s contribution to the earlier detection of breast cancer.

Studies have assessed the influence of test characteristics (such as search pattern, palpation, pressures, duration), patient characteristics (such as tissue density, and nodularity), and tumor characteristics (such as size, depth, mobility) on the CBE’s sensitivity and specificity. CBE techniques have been described and illustrated in several recent reviews; figures from one of these reviews are used to illustrate the recommendations presented here (Figures 1–3). These studies provide some basis for recommendations concerning the specific way CBE is performed. Not all aspects of visual inspection and palpation have been studied in controlled settings, however, and thus the following recommendations rely in part on the clinical expertise of the committee and the premise that visual inspection and palpation of every area of the breast and surrounding tissue will lead to identification of more breast masses.

Clinicians are encouraged to adopt and implement the following standards for performance of the CBE examination. Efforts to encourage widespread dissemination of these standards must be implemented as a partnership between clinicians and health care organizations.

CBE can contribute to the ability of health care professionals and women to detect some breast cancers and should lead to appropriate follow-up care. The committee recognizes that these recommendations are a first step in an incremental process of change and that many organizations and groups should be involved in defining and conducting such a process. Rather than develop a set of detailed algorithms and recommended procedures, the members chose to articulate a smaller group of general recommendations that embody several key themes and principles. In addition to appearing in this publication, these recommendations and accompanying text have been distributed to a wide range of stakeholders and interested parties to serve as a catalyst for further discussion and action. These recommendations provide a strong foundation for informing clinical practice, professional training, public education, and research efforts.

PATHOLOGIC FEATURES

The majority of invasive breast cancers are infiltrating ductal carcinomas. Infiltrating lobular carcinomas account for approximately 10% of breast cancers and have a prognosis similar to that of the infiltrating ductal type. Tubular, medullary, papillary, and colloid or mucinous carcinomas are uncommon but all have a prognosis better than that of infiltrating ductal or infiltrating lobular carcinomas. The phyllodes tumor (cystosarcoma phyllodes) is a rare, generally benign tumor composed of both epithelial and stromal elements. Phyllodes tumors may be bulky, rarely metastasize, do not spread to lymph nodes, and usually are treated by wide excision or simple mastectomy.

 Tubular carcinomas:

Tubular carcinoma. Three round tubular glands containing secretions are lined by a single layer of malignant cells (no myoepithelial layer) with minimal pleomorphism.

Medullary carcinomas:

Medullary carcinoma. Note the well-circumscribed boundary between the tumor and adjacent adipose tissue with focal lymphocytic infiltration

Papillary carcinomas:

Intracystic papillary carcinoma. A uniform population of neoplastic epithelial cells covers fibrovascular cores with very scant stroma. Myoepithelial cells are absent

Colloid or mucinous carcinomas:

Colloid (mucinous) carcinoma. Note clusters of cells with focal gland formation, surrounded by abundant blue-gray extracellular mucin

Infiltrating ductal carcinomas:

Infiltrating ductal carcinoma and ductal carcinoma in situ. Mammogram shows a round mass with ill-defined margins and malignant-appearing calcifications	Infiltrating ductal carcinoma. Mammogram shows two irregular masses with spiculated margins	Infiltrating ductal carcinoma, grade 3 (poorly differentiated). Note the prominent cellular pleomorphism, mitotic figures, and absence of tubule formation. This is a Papanicolaou-stained direct smear	Fine needle aspiration of infiltrating ductal carcinoma, cytologically high grade. Note large cells with prominent pleomorphism and overlapping/crowding without apparent tubule formation. This is a Papanicolaou-stained direct smear

Infiltrating lobular carcinomas:

Infiltrating lobular carcinoma. The neoplastic cells and their nuclei are uniformly small and round. Note the single file pattern of infiltration and the desmoplastic stroma

Breast biopsy specimens must be evaluated carefully, particularly now that breast-conserving surgery is selected increasingly as an alternative to mastectomy. Specimens should be processed so that their margins can be identified when visualized under the microscope. Coating specimens with India ink is a technique commonly used for identifying margins. Pathologists should record the dimensions of excised specimens, the size of the tumor, and its gross and microscopical relationships to the specific margins. Such other factors as the amount of associated ductal carcinoma in situ, lymphatic invasion, tumor grade, and histologic type (ductal, lobular, tubular, mucinous, medullary, inflammatory, etc.) may be important in assessing prognosis and selecting treatment.

An ultrasound-guided needle biopsy. Arrows point to needle	Fine needle aspiration of infiltrating ductal carcinoma, cytologically low grade. Note the intermediate-size cells with focal tubule formation. Many single cells are also present, typical of invasive carcinoma	Fine needle aspiration of infiltrating ductal carcinoma, cytologically high grade. Note large cells with prominent pleomorphism and overlapping/crowding without apparent tubule formation. This is a Papanicolaou-stained direct smear	Fine needle aspiration of lobular carcinoma. The Papanicolaoustained direct smear contains many dyshesive cells (cells appear singly rather than in glands or sheets). The cells are small and some have a “signet ring” morphology (intracytoplasmic mucin droplets that push the nucleus to the periphery of the cell)

The two types of carcinoma in situ—lobular and ductal—differ in a number of ways. In both types, malignant-appearing cells are seen under the microscope, but the cells are not invading outside of the lobular or ductal lumen.

Lobular Carcinoma In Situ

Lobular carcinoma in situ (LCIS) never forms a palpable mass, rarely is the cause of an abnormality on a mammogram, and usually is found accidentally on biopsy of some other lesion. LCIS occurs diffusely throughout both breasts and is associated with approximately a 10% to 15% risk of invasive cancer in each breast. The risk of invasive cancer for the breast contralateral to that undergoing biopsy is the same as for the breast with biopsy-proved LCIS. LCIS is viewed as a risk factor for subsequent breast cancer and is related more closely to atypical hyperplasia than to ductal carcinoma in situ (DCIS). Patients with LCIS are given one of two options: observation with careful follow-up or bilateral mastectomies. Most women select observation.

Lobular carcinoma in situ. The lobule is filled and expanded by a uniform population of small cells

Ductal Carcinoma In Situ

DCIS differs from LCIS in that it may form a mass, although most often today it is diagnosed by biopsy for microcalcifications seen on mammography. Usually, DCIS is unilateral and frequently is found in only one quadrant of one breast. The risk for subsequent cancer is primarily in the quadrant that has undergone biopsy if the DCIS is not eradicated adequately. The natural history of DCIS is not well understood, and it remains unclear how often such lesions progress to invasive cancers. On the basis of nuclear differentiation and the presence or absence of necrosis, several different systems have been devised to divide DCIS into three groups: high-, intermediate-, and low-grade. These systems recognize that different DCIS lesions behave with different potential for microinvasion and for development of microvessel density and have different proliferative rates. Ultimately, a comprehensive system that includes both molecular markers of biological behavior and histologic features likely will provide a meaningful basis for diagnosis and treatment. At the present time, no single system is recognized universally, but the risk for recurrence is considerably lower with low-grade lesions than with high-grade lesions, regardless of whether postoperative irradiation is used.

Ductal carcinoma in situ. Mammogram demonstrates extensive fine calcification, malignant in appearance	Ductal carcinoma in situ. Specimen radiograph shows wire in place and comedo-type calcifications. The arrow indicates calcification at margin of specimen	Ductal carcinoma in situ, cribriform type. This duct is replaced by a uniform population of neoplastic cells, forming round back-to-back glands. Some of the glands contain dark blue microcalcifications

In the majority of cases, the diagnosis of DCIS can be established readily. Problems arise, however, in differentiating DCIS from lesions at both ends of the spectrum. On the benign end, distinguishing DCIS from atypical ductal hyperplasia can be difficult; on the opposite

end, distinguishing some cases of DCIS from DCIS with focal stromal invasion can be difficult. In some instances, DCIS can resemble LCIS.

Mastectomy, long considered the standard treatment for DCIS, is associated with local tumor control and survival rates approaching 100% but is likely to represent overtreatment for many patients. DCIS appears to be a disease of one ductal system. Frequently, it is multifocal within a small area close to the indexlesion and rarely is multicentric or present in different parts of the breast distinct and at a distant from the indexfocus. In most cases, the disease was confined to one quadrant. These observations provided a rationale for breast-conserving treatment. Eight-year results from a randomized National Surgical Adjuvant Breast and Bowel Project trial (NSABBP-17) showed that local recurrences had been reduced by 55% and that invasive cancers have been reduced by 71% for patients receiving radiotherapy and wide excision as compared with wide excision alone.

A reasonable assumption is that low-grade DCIS identified by small areas of microcalcifications and excised with widely negative margins should be treated adequately without radiotherapy. However, selection criteria still are evolving. High-quality mammograms and careful margin assessment are essential to achieve low recurrence rates, regardless of whether the treatment includes radiotherapy. Axillary node dissection is not a standard of care at this time. For patients with extensive high-grade DCIS in which the risk of microinvasion or frank invasion is high, lower axillary dissection may be recommended. Typically, axillary dissection is not recommended for patients with limited DCIS treated with a breast-conserving approach because of the extremely low probability of nodal metastases.

A large randomized trial (NSABBP-24) demonstrated that the addition of tamoxifen to lumpectomy or lumpectomy and radiotherapy further reduced the risk of invasive and noninvasive local recurrences and of the incidence of contralateral breast cancers.

TRADITIONAL TREATMENTS

Early-stage breast cancer

• Surgery: Breast preservation with lumpectomy with radiation is the preferred treatment.
• Radiation: As a part of the breast-coserving treatment (lumpectomy), breast radiation is performed with 4 500 to 5 000 cGy boost to tumor-excision site.
• Systemic chemotherapy: Combination chemotherapy can reduce the annual risk of death by 20%, and in 10 years produces an absolute improvement in survival of 7% to 11% in women younger than 50 years.
• Hormone therapy: Tamoxifen is a selective estrogen-receptor modulator (SERM), can decrease the risk of recurrence by 42% and the absolute risk of death by 22% in patients with ER-positive tumors. Combination of tamoxifen with chemotherapy can cause a 25%-30% reduction in recurrence, compared with chemotherapy alone.

• Initial surgery is only used to biopsy to confirm the diagnosis and to identify the receptor status.
• Resection operation is done after the best response to preoperative chemotherapy.
• Neoadjuvant (primary) chemotherapy produces the tumor shrinks by 50% and allows surgical resection with clear margins in more than 65% of the women treated.
• Radiation to chest wall and supraclavicular area is done after surgery.

• Surgery and /or radiation may be used for local control.
• Hormone agents may be used as the first-line therapy in patient with positive hormone receptor.Hormone agents used are:

1. SERM with combined estrogen agonist and estrogen antagonist activity

2. Tamoxifen (Nolvadex), 20 mg/day, p.o.

3. Toremifene (Fareston), 60mg/day p.o.

5. Megestrol acetate (Megace), 40 mg/dose p.o. 4 times daily

Anastrozole(Arimidex), 1mg/day p.o.

Letrozole(femara), 2.5mg/day p.o.

Aminoglutethimide, 250 mg/dose p.o. 4 times daily;

hydrocortisone replacement to offset cortisol suppression associated with aminoglutethimide.

Leuprolide (Lupron Depot), 7.5mg/dose,i.m. monthly,OR

Leuprolide (Lupron Depot), 22.5mg/dose i.m. every 3 months, OR Leuprolide (Lupron Depot), 30mg/dose i.m. every 4 months

Goserelin (Zoladex), 3.6mg/dose,s.c. implant into the abdomen wall every 28 days OR

Goserelin (Zoladex), 10.8mg/dose,s.c. implant into the abdomen wall every 12 weeksUsed in patients who have tumors that express either ER or PR receptors or both receptors

 Chemotherapy may be used as the initial treatment in hormone receptor-negative patients.

Commonly used chemotherapy regimens are

AC: Dororubicin, 60mg/m2 i.v. on day 1 (total dose/cycle, 60mg/m2);

Cyclophosphamide,600mg/m2 i.v., on day 1 (total

dose/cycle, 600mg/m2);

Treatment cycles are repeated every 21-28 days depending on hematology recovery.

CMF: Cyclophosphamide, 100mg/m2 per day p.o. for 14 days, day 1-14(total dose/cycle,1 400mg/m2);

Methotrexate (MTX), 40mg/m2 per dose i.v. for two doses, day 1 and 8(total dose/cycle,20mg/m2)

5-FU, 600mg/m2 per dose i.v. for 2 doses,day1 and 8 (total dose/cycle 1,200mg/m2)

Treatment cycles are repeated every 28 days.

AC-P: Dororubicin, 60mg/m2 i.v. on day 1 (total dose/cycle, 60mg/m2);

Cyclophosphamide, 600mg/m2 i.v.,on day 1′4 cycles (total dose/cycle, 60mg/m2)

Followed by

Paclitaxel 175mg/m2 per dose i.v. over 3 hours every 3 weeks′4 cycles (total dose/cycle,175mg/m2);

Treatment cycles are repeated every 21 days.

Recurrent breast cancer

• For local recurrence surgical excision and radiation are choice.
• Chemotherapy and hormone therapy are as for metastatic breast cancer.

Trastuzumab (HerceptinTM)

Principle:

Indication: metastatic breast cancer with tumor overexpresses HER2/neu protein (3+ by immunohistochemistry). About 30% of the patients overexpress HER2/neu.

Regimen: Initial dosage is 4mg/kg i.v. over 90 minutes, followed at weekly intervals by maintenance with 2mg/kg i.v. over 30 minutes if the initial infusion rate was well tolerated.

Adverse effects: Common adverse effects during administration include fever and chills in up to 40% of patients. Mild to moderate symptoms may be successfully treated with acetaminophen, diphenhydramine, and meperidine (12.5-25 ng/dose i.v. or i.m.) with or without interrupting or slowing trastuzumab administration. Preexisting cardiac disease and cardiomyopathies associated with prior treatment (e.g., anthracycline drugs and radiation to the chest) may be exacerbated by trastuzumab.