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Reviewing prognostic factors in breast cancer management

Ideally, breast cancer is managed by a multidisciplinary team who, by looking at the big picture, can give the patient the best possible prognosis and quality of life.

Margie Glissmeyer, MS, PA-C

Margie Glissmeyer works in surgical oncology at Surgical Associates, Portland, Oregon. She has indicated no relationships to disclose relating to the content of this article.

According to the most recent estimates, a woman’s chance of developing breast cancer in the course of her lifetime is 1 in 8, and breast cancer accounts for one of every three cancers diagnosed in women in the United States.¹ More frequent screening and ever-improving imaging techniques are making it possible to diagnose more breast cancers when they are in situ,^2,3 but the majority of these cancers still manifest themselves when they have already become invasive. After the diagnosis of invasive breast cancer has been made, many factors determine the treatment and prognosis. This article reviews the primary prognostic factors and their clinical implications.

STAGING

The first important prognostic factors in the treatment of breast cancer are tumor size and whether lymph nodes and/or distant metastases are involved. Most surgeons evaluate lymph node status using sentinel lymph node mapping, a technique that involves injections of radioactive tracer and dye to locate and remove the sentinel node(s), which are the ones most likely to contain metastatic cells. These nodes are analyzed immediately by a pathologist. If the sentinel nodes are negative, no further lymph nodes are removed. If any of the sentinel nodes are positive, most surgeons perform complete axillary dissection. Research has shown that sentinel node biopsy is a safe way to gain accurate staging information while protecting many women from the morbidity associated with a full axillary node dissection.⁴

After tumor size and nodal involvement have been accurately determined, the tumor-nodes-metastasis (TNM) staging system is used (see Table 1). Survival rates based on stage vary somewhat, according to the source cited, but all sources agree that the prognosis for a woman with a stage 0 or stage 1 breast cancer is excellent and the prognosis for patients with distant metastases is grim (see Table 2).

Clinically, the stage of cancer has implications beyond overall survival. Stage 0 to early stage 1 tumors are generally managed using surgery, radiation, and hormonal therapy, whereas tumors larger than 1.5 to 2 cm, regardless of other prognostic factors and of the presence or absence of locally advanced disease, are generally treated with systemic chemotherapy. A positive lymph node, no matter what the tumor size or other prognostic factors, is also usually interpreted as an indication for chemotherapy.

HORMONE RECEPTORS

Another important prognostic factor is hormone receptor status. Most breast cancers are estrogen-receptor and/or progesterone-receptor positive. In hormone-receptor positive breast cancer, estrogen, progesterone, or both bind onto cancer cells in a lock and key fashion and encourage the cells to proliferate. Hormone-receptor positive breast cancers carry a much better prognosis because they can be treated with antihormonal agents such as tamoxifen or the newer aromatase inhibitors.^5,6

Tamoxifen is an antiestrogen medication whose exact mechanism of action is unknown. It is believed to work primarily as an antagonist, blocking the estrogen receptors and, therefore, depriving breast cancer cells of estrogen. Since tamoxifen (unlike aromatase inhibitors) works when ovarian function is intact, it is the treatment of choice for all premenopausal patients with hormone-receptor positive breast cancers. Tamoxifen carries a small but real increased risk of endometrial cancer and thromboembolic events, so personal and family history affect the decision to use it. Clinicians should take care to remember these increased risks when seeing patients at primary care visits.

The aromatase inhibitors, such as anastrozole, are a newer generation of antihormonal agents that can be used only in postmenopausal women. The primary source of circulating estrogen after menopause occurs through the conversion of adrenal adrostenedione to estrone by aromatase. Blocking aromatase activity significantly reduces the amount of circulating estrogen and, therefore, the amount of estrogen that is available to breast cancer cells.

Recent research suggests that aromatase inhibitors are superior to tamoxifen, prompting some premenopausal women with breast cancer to make the decision to undergo oophorectomy.^7-9 Data presented at the San Antonio Breast Cancer Symposium in 2005 show that in postmenopausal women, using a sequencing method of 2 years of tamoxifen followed by 3 years of anastrozole is superior to 5 years of tamoxifen, with a 32% reduction in the risk of recurrence.¹⁰ Evolving evidence also suggests that adding an aromatase inhibitor after a full 5 years of therapy with tamoxifen may increase disease-free survival, although not overall survival.

Aromatase inhibitors increase the risk of osteoporosis and, therefore, fracture. It is essential that all women taking aromatase inhibitors have their bone density monitored, take calcium with vitamin D, and take bisphosphonates if indicated.

Tamoxifen and the aromatase inhibitors are oral agents generally prescribed by medical oncologists. The primary side effects are menopausal symptoms, particularly hot flashes; arthralgias also occur and seem to be associated primarily with the aromatase inhibitors. Overall, however, these agents are well-tolerated. Use of aromatase inhibitors in hormone-receptor positive breast cancers reduces the risk of recurrence better than chemotherapy does, although systemic chemotherapy may still be indicated. When it is, patients are placed on tamoxifen or an aromatase inhibitor after chemotherapy is completed. The implications of estrogen-receptor negative and progesterone-receptor positive breast cancer are less well understood, but antihormonal treatment is often used in patients with these tumors as well.

Hormone-receptor negative cancers have a worse prognosis because antihormonal therapy cannot be used in treatment. Patients with hormone-receptor negative tumors receive traditional systemic chemotherapy, but their survival rates are not as high as for patients with hormone-receptor positive breast cancers.¹¹

HER2/NEU OVEREXPRESSION

Overexpression of the HER2/neu protein is another important prognostic factor in the management of patients with breast cancer. HER2/neu is a gene found on all human cells and helps to regulate cell growth. In approximately 20% to 30% of breast cancers, this gene causes overexpression of the HER2/neu protein, leading to increased cell growth and, consequently, to a more aggressive cancer. These cancers are said to be HER2/neu-positive. They have a poorer response to standard chemotherapy and are associated with a significantly worse outcome.^12,13 However, the drug trastuzumab, a relatively new agent, offers new hope for patients with HER2/neu-positive breast cancers.

Trastuzumab is a targeted monoclonal antibody that works by identifying cells with HER2/neu overexpression and binding to the HER2 receptors, slowing the growth of these cells. In the landmark study published in the New England Journal of Medicine in 2001, patients with metastatic disease were given trastuzumab in addition to the traditional anthracycline/cyclophosphamide or paclitaxel chemotherapy, with the group taking trastuzumab showing an 11% increase in survival at the end of 1 year.¹⁴ The follow-up phase 3 trials looking at the use of trastuzumab in patients with early-stage HER2/neu-positive breast cancers were stopped early after preliminary joint interim analysis demonstrated an improvement in the primary end point of disease-free survival and overall survival. According to preliminary data presented at the American Society of Clinical Oncology meeting in 2005, the addition of trastuzumab to chemotherapy showed a 33% 2-year decrease in and a 52% reduction in recurrence for patients receiving trastuzumab.^15,16

Trastuzumab is available only as an infusion administered over the course of 30 minutes. Current practices are generally to give the drug weekly for 1 year, but the optimal length of treatment has not yet been determined. Patients seem to tolerate treatment well, although those receiving trastuzumab have an increased risk of cardiotoxicity compared to patients receiving standard chemotherapy alone.¹⁵ Baseline cardiac function is assessed before treatment and reassessed if symptoms develop. Cardiotoxicity does require that trastuzumab be discontinued in some patients, but this agent is nonetheless an exciting advancement in the treatment of aggressive breast cancers.

MIB/KI-67

The majority of pathology reports will also include the results of testing for Ki-67 antigen expression using MIB-1 antibody. This test measures the cell proliferation rate in the tumor. Based on pathologic features, the tumor is assigned a designation of low, intermediate, or high proliferation. From a prognostics perspective, a low proliferative rate is associated with a lower risk of disease recurrence, and a high MIB is associated with a higher risk of recurrence and the development of distant disease.^17,18

The advent of more sophisticated diagnostics—such as Oncotype DX, a multigene assay that predicts recurrence risk in women with estrogen-receptor positive, node-negative breast cancer¹⁹—and the increasing importance placed on hormone-receptor and HER2/neu status as treatments emerge have decreased the importance of MIB as an independent factor in treatment and prognosis. However, the proliferative rate is still looked at as a piece of the overall picture when making clinical decisions concerning adjuvant therapy.

GRADE

The final piece of information found on most pathology reports is the grade of breast cancer. Pathologists use the Scarff-Bloom-Richardson system to determine the grade, with grade 1 being well-differentiated and grade 3 being poorly differentiated. The grade of breast cancer is an important indicator of aggressiveness and overall prognosis.^20,21 Independent of other factors, the 5-year survival between grade 1 and grade 3 breast cancers varies by approximately 45%.²² Clinically, grade is generally used as another indication of how aggressive to be with adjuvant therapy. For instance, a stage T1N0 tumor that is grade 3 would be more likely to be treated with systemic chemotherapy than the same stage tumor if it is grade 1.

IN SITU CANCERS

In situ breast cancers can be divided into two categories: ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS).

Ductal carcinoma in situ is a stage 0 breast cancer. Treatment decisions are made using the Van Nuys prognostic index, which is a scoring system that takes size of tumor, grade, and margins into account.²³ In 2003, an update was made to the Van Nuys prognostic index to include age²⁴ (see Table 3). Based on the score, patients are advised to undergo lumpectomy only, lumpectomy with radiation, or simple mastectomy.

Since DCIS by definition cannot have spread outside of the ducts, the nodes are not assessed at the time of surgery. However, most surgeons will perform a sentinel node biopsy when the patient is undergoing mastectomy for DCIS because it is always possible to find invasive components of the tumor on final pathology. At most institutions, DCIS tumors are now tested for estrogen and progesterone receptors as well. Many patients, particularly younger ones, are encouraged to begin taking antihormonal therapy after DCIS to decrease their risks both of recurrence and of developing another breast cancer.

Lobular carcinoma in situ is characterized as a risk factor, not a true carcinoma of the breast. Patients with a pathologic diagnosis of LCIS have roughly a 30% to 35% chance of developing breast cancer.^25,26 For this reason, many patients with LCIS are also being encouraged to undergo antihormonal therapy for risk reduction. A diagnosis of LCIS on core biopsy is an indication for lumpectomy for the sole purpose of confirming the absence of invasive carcinoma or DCIS associated with it, but radiation and more radical surgical procedures are not indicated.

OTHER FACTORS

A number of major prognostic factors are used in making clinical decisions and recommendations to patients with breast cancer. A large variety of patient presentations are possible. For some patients, the recommendations are straightforward, but for others, the decisions are not so simple. Factors including age,^27,28 comorbidities, and genetic predisposition²⁹ may influence clinical recommendations. Ideally, prognostic factors are looked at in terms of the big picture, and clinicians from surgery, radiation oncology, and medical oncology work together to come up with a multidisciplinary approach to treatment to give the patient the best possible overall prognosis and quality of life. JAAPA

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