American College of Physicians: Internal Medicine — Doctors for Adults ®

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Special Focus on Breast Cancer

From the October ACP Observer, copyright © 2006 by the American College of Physicians.

Click here for a PDF version of Special Focus: Breast Cancer

In this time of flux for physicians screening and treating patients for breast cancer, evidence seems to mount daily about everything from new imaging technologies to drug regimens for prevention and treatment.

“There are a lot of targeted agents on the horizon, with some already in active clinical use, such as trastuzumab and bevacizumab,” said Rebecca Davidson, MD, assistant professor of medicine in the division of hematology and oncology at the University of Pennsylvania and editorial consultant for the College’s PIER module on breast cancer.

Several of the most important breakthroughs recently have to do with prevention for women at increased risk of developing breast cancer. The National Cancer Institute’s STAR trial (Study of Tamoxifen and Raloxifene), which was one of the largest breast cancer prevention clinical trials ever, following nearly 20,000 women for an average of four years, found that raloxifene works as well as tamoxifen to reduce breast cancer risk by 50% in high-risk postmenopausal women, with a similar side-effect profile.

“It is a nice option for women who are not tolerating tamoxifen,” Dr. Davidson said. “I can feel comfortable recommending raloxifene to patients who have a concern about tamoxifen’s uterine cancer risk—as there may be less of a concern for this type of cancer on raloxifene. I also will use raloxifene preferentially in women who are osteoporotic.”

Also exciting, she said, is the evidence developing about the potential for using aromatase inhibitors for prevention in postmenopausal women. There are several ongoing cooperative group clinical trials investigating the potential benefit of these agents and whether they may prove to be even more beneficial than tamoxifen in preventing new breast cancer. In addition, the side effect profiles of aromatase inhibitors are different from tamoxifen and raloxifene, making them more attractive to women who have tried tamoxifen or raloxifene and had to stop due to symptoms.

There is also now “pretty compelling data” in favor of oophorectomy for women with BRCA1/2 gene mutations who have completed childbearing, she said. The surgery “not only reduces the risk of having ovarian cancer by 96%, but in premenopausal women it reduces the risk of having breast cancer by approximately 50%,” she explained. Another area under study has to do with different targeted agents for treatment, such as trastuzumab for women with HER2-positive tumors and a new breast cancer diagnosis and lapatinib for some metastatic cancers.

“This is the new horizon in breast cancer research,” Dr. Davidson said. "All agents begin with trials in the metastatic setting, then, if promising, progress into the adjuvant, neoadjuvant, and sometimes the prevention settings.”

According to the American Cancer Society, women living in the U.S. have a 13% lifetime risk of developing breast cancer, with 5%-10% of cases resulting from inherited mutations or alterations in the BRCA1 and BRCA2 genes, which are present in less than 1% of the population. Breast cancer accounts for one of every three cancers diagnosed in U.S. women. Incidence and death rates generally increase with age, but half of women are 61 or younger when diagnosed, and half are older.

This edition of ACP Special Focus is designed to help optimize your ability to diagnose, treat and manage patients with breast cancer.

PREVENTION

Address risk of developing breast cancer by asking about known risk factors such as current age, age at onset of menarche, age at first live birth and family history. If the patient is at increased risk or older than age 60, consider recommending a five-year course of oral tamoxifen (20 mg/d).

The Breast Cancer Risk Assessment Tool is available online from the National Cancer Institute. The tool, based on the Gail model, uses a woman's personal medical history (number of previous breast biopsies and the presence of atypical hyperplasia in any previous breast biopsy specimen), her reproductive history (age at the start of menstruation and age at the first live birth of a child), and the history of breast cancer among her first-degree relatives to estimate her risk of developing invasive breast cancer over specific periods of time.

The NCI tool has been shown to predict average risks of breast cancer in groups of women with the same risk factors and age. However, keep in mind that the Gail model has been validated only for white women. Some studies suggest that the tool underestimates risk for black women, and research is ongoing as to how effective it is for other minority populations.

For women with a significantly higher risk of developing breast cancer because of family history or an inherited genetic predisposition such as BRCA1, BRCA2 or p53 gene mutations, discuss prophylactic mastectomy or, alternatively, aggressive screening, including annual MRI.

In addition, refer women with suspected or confirmed BRCA1 or BRCA2 mutations to genetic counseling and discuss prophylactic oophorectomy if they have completed childbearing. Alternatives include participating in an ovarian cancer screening trial or undergoing regular transvaginal ultrasound and CA125 testing.

SCREENING

Begin screening all women starting at age 20 in the following manner:

  • Age 20-39:
    • Encourage monthly self-examination.
    • Perform a clinical breast examination every three years.
  • Age 40 and up:
    • Perform a yearly clinical breast examination.
    • American Cancer Society guidelines recommend screening asymptomatic, average-risk women with mammography beginning at age 40 and every one to two years thereafter. There is ongoing debate about the merits of screening between ages 40 and 49. ACP guidelines on the issue are forthcoming.
    • Reserve specialized imaging such as ultrasound, scintigraphy with sestamibi or MRI for when mammography is inconclusive or abnormal.
  • For women at higher risk:
    • Begin screening five to 10 years earlier than the age when breast cancer occurred in a first- or second-degree relative.
    • For women with BRCA1 and BRCA2 mutations, start screening at age 25.
    • Refer to genetic counseling before genetic testing. A true-negative test result for BRCA1 or BRCA2 mutation in a high-risk family setting does not rule out other potential yet undetected genetic abnormalities, and these women may still have a higher than average risk for developing breast cancer.

DIAGNOSIS

Although breast cancer is increasingly identified through an abnormal mammogram, many women first present with asymptomatic palpable nodules or other breast irregularities. While age is the most important risk factor and breast cancer is more common in older women, be aware that the disease is frequently misdiagnosed in younger women as a benign process.

Perform a careful bilateral breast examination, including the supraclavicular/axillary nodal basin, in all women reporting new breast symptoms, clinical findings or an abnormal mammogram. Look for potential physical changes such as breast asymmetry, nipple inversion, skin edema and thickening and a new axillary or supraclavicular mass.

Obtain mammography (and ultrasound as needed) in women with any new breast symptom or abnormal finding on physical examination, such as new palpable lump or bloody nipple discharge. Use previous imaging studies as a comparison against any new studies, and recognize that a negative imaging evaluation does not rule out breast cancer.

If there is nipple discharge, obtain a cytology specimen. Inflammatory breast cancer is sometimes initially misdiagnosed as mastitis. If findings suggest mastitis, consider a skin biopsy if inflammatory signs have not improved after seven to 10 days of antibiotic therapy.

Other differential diagnoses include fibrocystic changes of the breast, fibroadenoma, breast abscess or hematoma and breast cyst. Use clinical evaluation, mammography, ultrasound and needle biopsy to distinguish between malignancy and benign breast disease.

Tissue diagnosis is essential for diagnosis and therapeutic management. Obtain tissue by core biopsy or cytology specimen by fine-needle aspiration from any suspicious breast mass or abnormal area noted on breast imaging, but be aware that fine-needle aspiration cannot differentiate between invasive and non-invasive cancer. Consider referring patients with mammographic abnormalities to an experienced breast-imaging radiologist for tissue sampling under ultrasound or mammogram guidance.

If a breast imaging specialist or surgeon recommends against obtaining a biopsy, ensure the patient understands the need for timely repeated imaging and careful follow-up. Benign cysts and most fibroadenomas do not required tissue diagnosis.

If a patient has an axillary nodal mass but no evidence of a primary breast tumor, refer the patient to a certified breast imaging facility for mammography, ultrasound or MRI. One-quarter of these lesions will be malignant, and most of these metastatic carcinomas are secondary to a silent breast cancer.

Proper staging is essential. Use the American Joint Committee on Cancer (AJCC) TNM Staging System. A combination of tumor size, axillary nodal status and presence or absence of metastatic disease forms the basis of the TNM staging system. Oncotype DX, a multigene assay to predict the likelihood of distant recurrence, is emerging as an alternative tool to predict a patient's prognosis and relative benefit from systemic chemotherapy.

The key preoperative studies needed before surgical resection of breast cancer are: bilateral mammography, chest X-ray, review of biopsy specimens and any laboratory studies as indicated by the patient’s age and comorbidities. Additional imaging studies in the absence of symptoms are not cost-effective.

A thorough pathologic evaluation of biopsy or surgical specimens will include information about histologic diagnosis, tumor size, adequacy of margins, extent of noninvasive component and lymph node evaluation. Immunohistochemistry studies should include estrogen and progesterone receptor status, HER2 staining or FISH testing for HER2 gene amplication. This information is needed to assess the adequacy of surgery and to determine the need for additional locoregional (radiation therapy) or systemic therapy with chemotherapy, hormonal therapy, or trastuzumab.

NON-DRUG THERAPY

Tumor size, location and clinical stage of the disease plus patient preference largely determine the choice between mastectomy and breast conservation. The main objective of breast conservation or immediate reconstruction with live tissue (muscle flap) or implant following mastectomy is preservation of body image and self-esteem without compromising breast cancer survival. Survival rates are similar for mastectomy and lumpectomy plus radiation. Additional costs of post-lumpectomy radiation are offset by the cost of reconstructive surgery post mastectomy.

In most cases, recommend lumpectomy and postoperative radiation therapy (which can be delayed for up to six months following surgery) when patients have focal disease and tumors are fairly small compared to breast size. Consider primary systemic chemotherapy to reduce tumor size and potentially allow breast conservation for patients who would otherwise require a mastectomy or in patients with locally advanced disease (e.g., tumors invading chest wall or skin). Inform women with evidence of metastatic disease at presentation that the primary goal of surgery is locoregional control—not cure.

A workup of invasive breast cancer staging should include axillary node assessment, except when there is stage 4 disease, to dictate subsequent choice of locoregional and systemic adjuvant therapy after resection. Use standard axillary lymph node dissection or sentinel node biopsy. Avoid routine axillary node assessment in patients with noninvasive (in situ) carcinoma.

Order radiation therapy following mastectomy when patients have close surgical margins, dermal invasion or four or more positive nodes. Be aware of long-term effects of post-mastectomy radiation therapy that may include cardiovascular toxicity.

For most women with ductal carcinoma in situ (DCIS), recommend breast conservation approaches. Reserve mastectomy for selected cases, such as when there is extensive, mutifocal, multiquadrant involvement, significant risk factors and personal preference.

DRUG THERAPY

For DCIS, recommend a five-year course of adjuvant tamoxifen following lumpectomy and radiation therapy to prevent development of a new breast cancer. Alternatively, consider enrolling postmenopausal women in a clinical trial comparing tamoxifen and an aromatase inhibitor.

Consider withholding adjuvant systemic therapy after surgery in patients with invasive disease and no axillary involvement and:

  • tumors <0.5 cm or microinvasion only;
  • favorable and less frequent invasive breast cancer histologic findings such as tubular, colloid, and medullary carcinomas measuring <1.0 cm;
  • ductal and lobular histologic findings, tumors measuring 0.6 to 1.0 cm with favorable features (no angiolymphatic invasion, low S-phase, or low histologic grade).

For most patients with invasive breast cancer (stages 1-3), recommend adjuvant systemic therapy with tamoxifen, three to six months of chemotherapy agents, or both in patients with:

  • tumors <2cm and no axillary node involvement (stage 1)
  • tumors >2 cm, positive axillary nodes, or both (stage 2)
  • involvement of internal mammary nodes, matted axillary adenopathy, inflammatory breast cancer, or all three (stage 3).

For postmenopausal women, consider an aromatase inhibitor instead of tamoxifen. HER2-positive patients may benefit from trastuzumab. Consider a five-year course of tamoxifen for patients with estrogen- or progesterone-receptor-positive disease, and a one-year course of trastuzumab for a HER2-positive patient. Age alone should not determine eligibility for adjuvant chemotherapy; older and younger women experience similar decreases in cancer mortality and recurrence.

Preoperative chemotherapy may be suitable for patients with operable breast cancer who are not initial candidates for breast conservation therapy because of a large tumor. A three-month anthracycline- or taxane-based regimen can shrink tumors 50%, allowing a small increase in the rate of breast conservation, although with similar overall survival. Preoperative treatment with trastuzumab is investigational only. In addition, in patients with large tumors or stage 3 disease receiving combined modality therapy, consider radiation before surgery if there are concerns about positive margins at surgery following primary systemic chemotherapy. A multidisciplinary approach improves five-year survival rates to 30%-60%, up from 10%-20% with local therapy alone.

For patients with widely metastatic breast cancer, which is incurable, emphasize palliation of symptoms, particularly control of pain, treatment of anemia, prevention of pathologic fractures and addressing psychosocial issues. Consider using single-agent chemotherapy or treating patients with hormone-receptor positive disease initially with hormonal therapy only. For patients with lytic bone disease, use radiation therapy or pamidronate or both.

Encourage patients to assume a primary role in their treatment planning, decisions about treatment options and recovery from surgery. Refer patients to specialists including radiologists, surgeons and medical oncologists, as needed because patients benefit from a multidisciplinary approach.

Instruct patients about the long- and short-term side effects of chemotherapy and prescribe an effective antinausea regimen. Discuss with patients long-term effects of adjuvant therapy, such as, in the case of tamoxifen, increased risks of endometrial cancer and thromboembolic disease. In the case of chemotherapy, discuss the possibility of cognitive or myocardial dysfunction (following anthracycline) and myeloid dysplasia/leukemia (following anthracycline and alkylating agents).

Anticipate the problems of lymphedema, which may occur in up to 20% of women after surgery. Minimize injections and blood pressure checks in the affected arm and refer patients to physical therapy. Recognize the symptoms of depression and fatigue and intervene early. Advise patients older than 40 of early menopause following chemotherapy and treat symptoms.

FOLLOW-UP

Stress to patients the importance of ongoing follow-up, including monthly breast self-examination, annual mammograms, and a schedule of alternate routine visits with members of the cancer care team every three to six months in the first two to three years after therapy, then six to 12 months for the next two years, and annually thereafter.

After five years, follow-up visits should be with a primary care provider. Other follow-up screening imaging studies or blood tests, including hemograms, blood chemistry studies, tumor market studies, chest X-rays and bone scans, are only necessary to evaluate specific complaints or symptoms suggesting disease recurrence. Recommend an exercise regimen to enhance emotional well-being after therapy.

Ask patients about new symptoms that may suggest recurrence, spread of the disease or complications from therapy, such as another breast mass, weight loss, fatigue, bone or abdominal pain and neurological symptoms. Early diagnosis of second malignancies is key to enhancing survival.

Follow standard cancer screening guidelines, particularly for gynecologic and lower gastrointestinal malignances, with period pelvic examination, stool guaiac test and lower bowel endoscopy.

Early detection of asymptomatic metastatic breast cancer does not affect survival, and the goal of treatment should be palliation of symptoms. Taxane-based chemotherapy alone or in combination with trastuzumab in HER2-postive disease may improve survival for 20%-30% of patients. Early radiation or orthopedic surgery may prevent paraplegia and bed-confining fractures.

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What imaging should you recommend?

The evidence is now in that digital mammography technology works better than film mammography in picking up asymptomatic small breast cancers in younger women with dense breasts.

But does its effectiveness justify its higher costs?

“If available, I think it should be preferentially ordered in young women with dense breasts,” said Rebecca Davidson, MD, assistant professor of medicine in the division of hematology and oncology at the University of Pennsylvania and editorial consultant for the College’s PIER module on breast cancer.

An editorial in the Oct. 27, 2005 issue of The New England Journal of Medicine by D. David Dershaw, MD, of the Memorial Sloan-Kettering Cancer Center in New York, agreed, but added that “good-quality screening mammography saves lives” regardless of “the way the image is stored.” Another study in the same issue found that the accuracy of digital mammography was “significantly higher than that of film mammography among women under the age of 50, women with heterogeneously dense or extremely dense breasts…and premenopausal or periomenopausal women.”

Since digital mammography equipment can cost up to four times as much as film mammography systems, only about 10% of imaging facilities in the U.S. offer it.

State-of-the-art technology isn’t the only way to improve screening mammography. Having skilled technicians do tests and specialized radiologists interpret images is also critical. In fact, explained Constance Lehman, MD, PhD, section head of breast imaging at the University of Washington Medical Center and the Seattle Cancer Care Alliance, “the most important message an internist can give to her patient is to go to a high-quality center with experience, and high-quality center doesn’t just mean the kind of equipment they have.”

For average-risk women, Dr. Lehman said primary care physicians should not recommend anything other than screening mammography. “We strongly discourage screening ultrasound or screening MRI,” she said. “It’s a waste of money, and we are going to have many false positives.”

For women at increased risk, however, she said, there is benefit to adding MRI to mammography as a screening tool—“as a complement, not as a replacement,” she said.

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