Stages 0 and I Breast Cancer

April 16, 2009

This chapter focuses on the diagnosis and management of early-stage breast cancer, ie, stages 0 and I disease. This is an important area, since more noninvasive and small breast cancers are being diagnosed due to the -increasing use of screening mammography. Treatment of these malignancies will continue to evolve as the results of clinical trials lead to further refinements in therapy.

This chapter focuses on the diagnosis and management of early-stage breast cancer, ie, stages 0 and I disease. This is an important area, since more noninvasive and small breast cancers are being diagnosed due to the -increasing use of screening mammography. Treatment of these malignancies will continue to evolve as the results of clinical trials lead to further refinements in therapy.

STAGE 0 BREAST CANCER

Stage 0 breast cancer includes noninvasive breast cancer-lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS)-as well as Paget’s disease of the nipple when there is no associated invasive disease.

LOBULAR CARCINOMA IN SITU

LCIS is nonpalpable, produces no consistent mammographic changes, and is often an incidental finding after breast biopsy performed for another reason.

The biologic behavior of LCIS continues to be an issue of debate. Most clinicians agree that it is a marker for increased risk for all types of breast cancer (both noninvasive and invasive).

Epidemiology and etiology

The incidence of LCIS has doubled over the past 25 years and is now 2.8 per 100,000 women. In the past, the peak incidence of LCIS was in women in their 40s. Over the past 3 decades, the peak incidence has increased to the 50s. The incidence of LCIS decreases in women who are in their 60s to 80s. It has been suggested that the increase in the age of peak incidence of LCIS is related to the use of hormone replacement therapy (HRT). It is also possible that the use of HRT prevents the usual regression of LCIS normally seen at the time of menopause.

Signs and symptoms

LCIS is nonpalpable and has no consistent features on breast imaging. Most often, LCIS is found in association with a completely separate mammographic abnormality or palpable mass.

Risk of invasive cancer

Approximately 20% to 25% of women with LCIS will develop invasive cancer within 15 years after the diagnosis of LCIS. More often, the invasive cancer is ductal in origin, and both breasts are at risk. At this point, there are no reliable molecular markers to determine which patients with LCIS will progress to invasive cancer.

Just as the incidence of LCIS has increased, there has also been an associated increase in the incidence of cases of infiltrating lobular carcinoma in postmenopausal women. The increase in invasive lobular carcinoma peaks in women in their 70s.

Pathology

LCIS appears to arise from the terminal ductlobular apparatus, and the disease tends to be multifocal, multicentric, and bilateral. Subsequently, other types of LCIS have also been described and include pleomorphic LCIS. This entity tends to be associated with infiltrating lobular carcinoma, and the cytologic features are similar to those of intermediate or high-grade DCIS. Pleomorphic LCIS may be more aggressive, with a higher likelihood of progression to invasion than classic LCIS.

Treatment options

The management of LCIS is continuing to evolve since the disease appears to be heterogeneous. Presently, treatment options include close follow-up, participation in a chemoprevention trial, tamoxifen, or bilateral prophylactic total mastectomy with or without reconstruction. At present, the decision for a given treatment will depend upon the patient's individual risk profile for DCIS or invasive breast cancer after careful counseling. In the future, treatment decisions may be based upon an analysis of a series of molecular markers, which can separate those patients with a low risk for invasion from those who are at high risk for disease progression.

DUCTAL CARCINOMA IN SITU

DCIS is being encountered more frequently with the expanded use of screening mammography. In some institutions, DCIS accounts for 25% to 50% of all breast cancers.

Epidemiology

DCIS, like invasive ductal carcinoma, occurs more frequently in women, although it accounts for approximately 5% of all male breast cancers. The average age at diagnosis of DCIS is 54 to 56 years, which is approximately a decade later than the age at presentation for LCIS.

Signs and symptoms

The clinical signs and symptoms of DCIS include a mass, breast pain, or bloody nipple discharge. On mammography, the disease most often appears as microcalcifications. Because these microcalcifications are nonpalpable and are not always associated with a mass, DCIS is often discovered with mammography alone. Approximately 5% of patients who present with pathologic nipple discharge will have underlying breast cancer, and many of them will have DCIS alone.

Risk of invasive cancer

The risk of developing an invasive carcinoma following a biopsy proven diagnosis of DCIS is between 25% and 50%. Virtually all invasive cancers that follow DCIS are ductal and ipsilateral and generally present in the same quadrant within 10 years of the diagnosis of DCIS. For these reasons, DCIS is considered a more ominous lesion than LCIS (which is considered a marker for risk) and appears to be a more direct precursor of invasive cancer.

Pathology

A variety of histologic patterns are seen with DCIS, including solid, cribriform, and papillary. Some researchers have divided DCIS into two subgroups: comedo and noncomedo types. As compared with the noncomedo subtypes, the comedo variant has a higher proliferative rate, overexpression of human epidermal growth factor receptor 2 (HER2/neu), and a higher incidence of local recurrence and microinvasion. DCIS is less likely to be bilateral and has approximately a 30% incidence of multicentricity.

Treatment of noninvasive breast carcinoma

DUCTAL CARCINOMA IN SITU

Breast-conserving surgery

Breast-conserving surgery, followed by radiation therapy to the intact breast, is now considered the standard treatment of DCIS. Because the incidence of positive lymph nodes after axillary lymph node dissection for DCIS is ~1% to 2%, axillary dissection is not indicated in most instances.

The most important factor in determining local tumor control within the breast is margin status. A surgical margin of 1 mm has been associated with a 43% chance of having residual disease at the time of reexcision. When a surgical margin of 10 mm can be obtained, there is an extremely low rate of recurrence (4%). A 10-mm surgical margin may not be practical, however, when trying to provide a good cosmetic outcome. When breast-conserving therapy is used alone (without irradiation), a margin of at least 10 mm is required, and the tumor should be small (< 1 cm) and a noncomedo type. Although a wide margin is always desirable, narrower margins are acceptable for DCIS when radiation therapy is used after lumpectomy.

Sentinel node biopsy

The sentinel lymph node is the first node in the draining lymphatic basin that receives primary lymph flow. The technique of sampling the first draining lymph node was initially described in the management of patients with melanoma to determine who would benefit from regional lymph node dissection and was performed using a vital blue dye. This same technique has been used in patients with breast cancer, and sentinel lymph node biopsy represents a minimally invasive way to determine whether the axilla is involved with disease. The precise methods for identifying the sentinel lymph node (filtered vs unfiltered Tc-99m sulfur colloid and/or blue dye) and assessing the node (hematoxylin and eosin staining vs immunohistochemistry [IHC] vs polymerase chain reaction [PCR]) are being studied.

When blue dye is used, it can be injected into the breast parenchyma at the primary tumor or subareolar site. The radioactive tracer can be injected subdermally or intraparenchymally at the site of the primary tumor or in the subareolar location. The site and technique of injection will be based upon individual patient factors, including the type and location of the previous breast biopsy.

When lymphatic mapping and sentinel lymph node biopsy are performed, a blue vital dye and/or a

radioactive tracer (generally technetium-labeled sulfur colloid) can be used. When a radiotracer is used, lymphoscintigraphy can also be performed to aid in locating the sentinel node. When a sentinel node biopsy is performed using blue dye, the axillary surgery should be performed carefully to avoid disrupting the blue-stained afferent lymphatic channels. When a radioisotope is used, a hand-held gamma counter is used to locate the sentinel node.

Axillary lymph node dissection is not routinely recommended for patients with DCIS. Recently, however, investigators have used sentinel lymph node biopsy to determine whether individuals with DCIS may harbor occult nodal metastases. Current studies have identified metastatic disease to the axillary nodes in up to 12% of patients who have undergone sentinel lymph node biopsy. Despite this relatively high percentage of positive sentinel nodes, recurrence in the nodal basins is rare (about 2%). Based on this and recent work, there is no indication for routine sentinel lymph node biopsy in patients with DCIS.

Factors associated with an increased risk of axillary metastasis with a diagnosis of DCIS are extensive DCIS requiring mastectomy, suspicion of microinvasion, DCIS associated with a palpable mass, and evidence of lymphovascular permeation or invasion seen on review of the slides. These factors likely are associated with a preoperatively nondiagnosed invasive component. However, for patients diagnosed with DCIS who are scheduled for mastectomy, sentinel lymph node sampling, prior to mastectomy, is a reasonable practice. In the event that an occult invasive cancer within the mastectomy is found, a negative sentinel node would be reassuring and perhaps would make it possible to avoid follow-up axillary dissection.

Patients whose sentinel node biopsy is negative do not require a complete node dissection, because the risk of an axillary recurrence is extremely low. Many institutions are using IHC in the evaluation of the sentinel node. When there is no evidence of metastatic disease by routine hematoxylin and eosin staining and the node is IHC-negative, the node is considered pN0(i−). When the routine staining is negative and isolated tumor cells are seen on IHC alone and no tumor cluster is greater than 0.2 mm, the node is staged as pn0(i+). Themajority of the data suggest that there is no effect on survival, the patient is considered node-negative, and a complete axillary node dissection is not warranted. Some authors suggest, however, that the presence of isolated tumor cells on sentinel node biopsy has been associated with the presence of additional disease within the remaining axillary nodes and a decreased survival when an axillary node dissection was not performed. Additional studies will be necessary to resolve this conflict. If the focus of metastatic disease is greater than 0.2 mm but less than 2 mm, the node is staged as pN1mi. In this instance, consideration should be given to a complete axillary node dissection or the administration of axillary radiation. The likelihood that additional nodal disease will be identified in the axilla increases with the size of the primary tumor.

Adjuvant radiation therapy

Retrospective series of patients with DCIS, as well as subsets of patients with early invasive cancer, have been treated with conservative surgery alone, omitting radiation therapy to the intact breast. In addition, several prospective, randomized trials have attempted to address this issue of omission of breast irradiation for both invasive cancer and DCIS. It is clear from all of these series that omission of breast irradiation results in a significantly higher ipsilateral breast tumor recurrence rate but has not, as yet, had an impact on overall survival.

Two large prospective randomized trials have demonstrated a significant reduction in local relapse with the use of postlumpectomy irradiation in treatment of DCIS. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17, the local recurrence rate at 8 years was reduced from 27% to 12% with postlumpectomy irradiation.

Similar results have been reported by a European cooperative group study of 1,010 women with DCIS randomly assigned to receive either 50 Gy of radiotherapy to the whole breast over 5 weeks or no further treatment. With a median follow-up of 4.25 years, the 4-year local relapse-free rate was 91% in the radiotherapy arm versus 84% in the observation arm. Hazard ratios with postexcision radiotherapy were 0.62 for all local relapses, 0.65 for DCIS recurrences, and 0.60 for noninvasive recurrences.

Both trials showed that radiotherapy reduces the risk of both noninvasive and invasive recurrences. Identification of a subgroup of patients who did not benefit from postlumpectomy irradiation has not as yet been clearly defined.

The Van Nuys Prognostic Index (VNPI), based on tumor size, grade, presence of necrosis, and width of the excision margin, is an algorithm commonly used to predict local recurrence after breast-conserving surgery for DCIS. In some series, VNPI lacked discriminatory power for guiding further patient management. In studies performed by this group, it appears that the width of the excision margin is the most important predictor of local recurrence after breast-conserving surgery for DCIS.

One study demonstrated acceptable local control in patients with DCIS treated by excision alone, provided that wide negative margins were obtained. In this retrospective series of 469 patients, radiation therapy did not lower the local recurrence rate in patients with wide (≥ 10 mm) negative margins but did produce a significant benefit in patients with close (≤1 mm) margins. The authors concluded that radiation therapy is unlikely to benefit patients with wide negative margins and small tumors. These findings need to be confirmed in prospective, randomized trials.

Although there may be some patients for whom wide excision alone is appropriate therapy, the available literature has not consistently identified the specific subgroup of patients. Clearly, the omission of radiation therapy in subsets of patients remains a controversial issue worthy of further investigation. It is hoped that ongoing randomized studies will help to resolve some of the conflicts generated by selective, retrospective studies.

Two trials have addressed the need for postlumpectomy radiation therapy (RT) in older women with breast cancer. Both studies randomized patients, following lumpectomy and adjuvant hormonal therapy, to receive RT or observation. Both studies confirmed statistically significant improvements in local control with RT, and local relapse rates were acceptable in carefully selected patients. The authors concluded that selected elderly patients may be treated with hormonal therapy alone (without RT) following breast-conserving therapy.

Adjuvant tamoxifen therapy

Adjuvant chemotherapy is not routinely employed for patients with DCIS.In NSABP B-24, 1,804 women with DCIS treated with lumpectomy and irradiation were randomly assigned to receive placebo or tamoxifen. At a median follow-up of 74 months, women in the tamoxifen group had fewer breast cancer events than those in the placebo group (8.2% vs 13.4%; P = .0009). Tamoxifen decreased the incidence of both ipsilateral and contralateral events. The risk of ipsilateral invasive cancers was reduced by tamoxifen, regardless of the presence or absence of comedo-necrosis or margin involvement.

In a more recent analysis of NSABP B-24, it was found that the benefit from tamoxifen is derived exclusively by patients with hormone receptor-positive disease. Based on these results, tamoxifen should be considered as adjuvant therapy for patients with hormone receptor-positive DCIS. The use of tamoxifen for the prevention of secondary breast cancers in women at high risk for breast cancer, which includes women previously diagnosed with DCIS, has led some clinicians to consider the use of tamoxifen in women diagnosed with DCIS.

STAGE I BREAST CANCER

Stage I breast cancer ranges from microinvasive tumors (≤ 0.1 cm) to tumors ≤ 2 cm without evidence of spread to the regional lymph nodes.

Pathology of invasive breast cancer

Ductal carcinoma Most cases of invasive carcinomas of the breast are ductal in origin. Of the different histologic subtypes of ductal carcinoma that have been described, tubular, medullary, mucinous (colloid), and papillary subtypes have been associated with a favorable outcome.

Lobular carcinoma Approximately 5% to 10% of invasive breast cancers are lobular in origin. This histology has been associated with synchronous and metachronous contralateral primary tumors in as many as 30% of cases.

Treatment

SURGICAL AND RADIATION TREATMENTS

Multiple studies have demonstrated that patients with stage I breast cancer who are treated with either breast-conserving therapy (lumpectomy and radiation therapy) or modified radical mastectomy have similar disease-free and overall survival rates.

Breast-conserving therapy

Extent of local surgery The optimal extent of local surgery has yet to be determined and, in the literature, has ranged from excisional biopsy to quadrantectomy. A consensus statement on breast-conserving therapy issued by the National Cancer Institute (NCI) recommended that the breast cancer be completely excised with negative surgical margins.

The extent of axillary surgery also continues to evolve. In recent years, patients with early-stage breast cancer who have clinically node-negative disease have the option to undergo sentinel lymph node biopsy rather than axillary node dissection. The present standard of care for patients with a positive sentinel node is complete nodal dissection. A study is under way to determine whether patients with a positive sentinel node require further axillary surgery.

Patient selection Specific guidelines must be followed when selecting patients for breast conservation. Patients may be considered unacceptable candidates for conservative surgery and radiation therapy either because the risk of breast recurrence following the conservative approach is significant

enough to warrant mastectomy or the likelihood of an unacceptable cosmetic result is high. Some patients who are candidates for breast conservation can undergo breast MRI to identify sites of additional disease within the breast that may preclude breast-conserving treatment, although this is not a standard for evaluation. Contraindications to breast-conserving surgery are listed in Table 1.

Risk factors for ipsilateral recurrence For patients undergoing conservative surgery followed by radiation therapy to the intact breast, the risk of ipsilateral breast tumor recurrence has been reported to range from 0.5% to 2.0% per year, with long-term failure rates varying from 7% to 20%. Risk factors for ipsilateral breast tumor recurrence include, but are not limited to, young age (< 35 to 40 years), an extensive intraductal component, major lymphocytic stromal reaction, peritumoral invasion, presence of tumor necrosis, and positive resection margins. After a wide excision has been performed, the specimen should be oriented and inked; the pathologist may then ink each margin a different color. If a positive surgical margin is present, the color-coded system will guide the reexcision to obtain negative surgical margins with the removal of the least amount of breast tissue possible.

Earlier studies demonstrated that an extensive intraductal component was a risk factor for local relapse. However, in subsequent reports, when negative surgical margins are achieved, patients with an extensive intraductal component can be safely treated with breast conservation. Although it is desirable to achieve negative surgical margins, the available data do not preclude the use of conservative treatment, provided that adequate radiation doses (> 6,000 cGy) to the tumor bed are employed. The role of the remaining risk factors previously cited in predicting recurrence is unclear, and patients should not be denied breast conservation because of their presence.

Cosmetic considerations include primary tumor size and location, overall breast size, total body weight, and a history of preexisting collagen vascular disease.

Tumor size and breast size are important in determining whether the patient will have an acceptable cosmetic outcome after surgical resection. Patients with large tumors with respect to breast size may consider neoadjuvant chemotherapy to reduce the size of the primary tumor and allow breast preservation. (See chapter 11 for discussion of neoadjuvant chemotherapy.)

Obese women with large, pendulous breasts may experience marked fibrosis and retraction of the irradiated breast, making a good to excellent cosmetic outcome less likely. Techniques of brachytherapy may prove beneficial for these women. Women in this situation can undergo bilateral reduction mammoplasty after the wide excision of the primary tumor site has been completed. The partial mastectomy specimen should be evaluated by the pathologist to ensure adequate resection margins. Radiopaque clips can be left to mark and identify the primary tumor site for the radiation oncologist. The follow-up mammograms will be more difficult to interpret due to scarring and radiotherapy effect.

Patients with collagen vascular disease may develop more severe reactions following radiation therapy. Although initial anecdotal reports demonstrated higher complication rates in patients with collagen vascular disease, a case-controlled study of patients with early-stage breast cancer showed higher complication rates only in those patients with scleroderma. Other case-controlled studies have also failed to demonstrate significantly higher complication rates in patients with collagen vascular disease undergoing radiation therapy. It appears that most patients without active significant collagen vascular diseases may be candidates for breast-conserving surgery and irradiation, although this approach remains controversial.

In some instances, it is necessary to excise skin to obtain a negative surgical margin. This does not necessarily preclude the patient from undergoing breast-conserving therapy and does not mean the patient should have a poor cosmetic outcome. When skin must be removed to obtain a negative surgical margin, complex skin closures, such as V-Y advancement flaps or Z-plasties, can be utilized to enhance cosmesis.

Patients with centrally located tumors Traditionally, patients who have centrally located tumors requiring excision of the nipple-areolar complex have not been offered the option of breast conservation. However, the cosmetic result achieved after local tumor excision that includes the nipple-areolar complex may not differ significantly from that obtained following mastectomy and reconstruction.

Furthermore, conservatively treated patients with sub-areolar lesions do not necessarily need to have the nipple-areolar complex sacrificed, as long as negative surgical margins can be achieved. However, if the complex is not removed, the remaining breast tissue and overlying skin remain sensate. Recent studies also indicate that the incidence of local recurrence is not increased when primary tumors in this location are treated conservatively.

Genetically predisposed breast cancer patients For women harboring germline mutations in BRCA1 or BRCA2, there are limited data regarding long-term outcome. Studies, to date, have shown acceptable local control rates in the short term and increased but acceptable rates of acute, subacute, and chronic normal tissue reactions with lumpectomy followed by radiation therapy. Women with germline BRCA1 and BRCA2 mutations, however, are at high risk for second primary tumors in the contralateral breast.

A study from Yale University demonstrated high rates of second primary tumors in the ipsilateral breast. This study suggests that if breast-conserving therapy is chosen, some prophylactic measures, such as selective estrogen receptor modulators or oophorectomy, might be considered to reduce the risk

of second primary tumors in the ipsilateral or contralateral breast. Other studies also indicate a trend toward higher rates of late local relapses in BRCA carriers. Further studies are clearly warranted to assess the long-term risks and benefits of breast-conserving strategies in women harboring mutations in BRCA1 and BRCA2.

Role of axillary lymph node dissection The role of axillary lymph node dissection in the management of breast cancer has been questioned, particularly when a patient with a clinically negative axilla is undergoing breast-conserving therapy. In most instances, the breast surgery is performed with the patient under local anesthesia and sedation on an outpatient basis. When axillary lymph node dissection is added, the surgery is performed with the patient under general anesthesia.

It has also been suggested that if the status of the nodes will not alter therapy, the dissection is unnecessary and the axilla can be treated with irradiation. On the other hand, if axillary lymph node staging is not performed, the patient will not be accurately staged and important prognostic information will be unavailable.

Patients who may not be candidates for sentinel node biopsy are women who are pregnant or breast-feeding and women who have had prior irradiation. A prior excisional biopsy does not preclude the use of lymphatic mapping and sentinel node biopsy. It has been suggested that sentinel node biopsy accurately evaluates the axilla, even in patients with tumors > 5 cm and in those who have been treated with neoadjuvant chemotherapy.

Once the sentinel node(s) have been identified, they can be sent to pathology for frozen section or touch-prep analysis.

Sensitivity and specificity In breast cancer, lymphatic mapping has been performed using a vital blue dye and/or lymphoscintigraphy. Studies have suggested that the success rate for identifying the sentinel node can be increased when these techniques are used in combination. The ability to identify the sentinel node can reach as high as 97% when blue dye and Tc-99m sulfur colloid are used together. When blue dye is used alone, the success rate is 83%, and when Tc-99m sulfur colloid is used alone, the success rate is 94%.

Results from a multi-institution practice have demonstrated that sentinel lymph node biopsy using dual-agent injection provides optimal sensitivity. In the study, 806 patients were enrolled by 99 surgeons for sentinel lymph node biopsy by single-agent (blue dye alone or radioactive colloid alone) or dual-agent injection at the discretion of the surgeons. All patients underwent complete level I/II dissection following the sentinel procedure. There were no significant differences in the identification of a sentinel node among patients who underwent single compared with dual-agent injection. However, the false-negative rate was 11.8% for single-agent versus 5.8% for dual-agent injections (P = .05).

The sensitivity and specificity of sentinel lymph node biopsy are high, and the likelihood of a false-negative result is extremely low. False-negative rates vary among series, ranging from 0% to 11%. In one series, in 18% of the cases where the frozen-section evaluation of the node was negative, the final pathologic evaluation revealed metastatic disease, and the patient ultimately required lymph node dissection. This potential result can be distressing to patients; however, they should be informed of this possibility at the time of the procedure.

Patients whose sentinel node biopsy is normal do not require a complete node dissection, because the risk of an axillary recurrence is extremely low. Many institutions are using IHC in the evaluation of the sentinel node. When there is no evidence of metastatic disease by routine hematoxylin and eosin staining and the node is IHC−, the node is considered pN0 (i−). When there are isolated tumor cells seen but no cluster is greater than 0.2 mm, the node is staged as pN0 (i+) and the patient does not require a complete node dissection. If the focus of metastatic disease in the node is greater than 0.2 mm but less than 2 mm, the node is staged as pN1mi. In this instance, consideration should be given to performing a complete axillary node dissection or axillary radiation therapy, unless the patient is participating in a clinical trial. The likelihood that nonsentinel lymph nodes will also contain metastatic disease increases as the size of the primary tumor increases.

Radiation therapy after breast-conserving surgery

Based on the results of a number of retrospective single-institution experiences, as well as several prospective randomized clinical trials, breast-conserving surgery followed by radiation therapy to the intact breast is now considered a standard treatment for the majority of patients with stage I or II invasive breast cancer.

Radiation dose and protocol Radiation therapy after breast-conserving surgery should employ careful treatment planning techniques that minimize treatment of the underlying heart and lungs. To achieve the optimal cosmetic result, efforts should be made to obtain a homogeneous dose distribution throughout the breast. Doses of 180 to 200 cGy/d to the intact breast, to a total dose of 4,500 to 5,000 cGy, are considered standard.

Additional irradiation to the tumor bed is often administered. Although the necessity of a boost to the tumor bed has been questioned, at least two randomized clinical trials have demonstrated a small but statistically significant reduction in ipsilateral breast tumor relapses with the use of a radiation boost to the tumor bed following whole-breast irradiation of 50 Gy. In one of these trials, involving more than 5,000 women randomized to receive either a 16-Gy boost to the tumor bed or not, a 3% absolute reduction in local relapse was seen with the use of the radiation boost (4.3% vs 7.3%; P < .0001). This effect was particularly evident in patients younger than age 50. The boost is directed at the original tumor bed with either electron-beam irradiation or an interstitial implant, to bring the total dose to 50 to 66 Gy.

Regional nodal irradiation For patients who undergo axillary dissection and are found to have negative nodes, regional nodal irradiation is no longer routinely employed. For patients with positive nodes, radiation therapy to the supraclavicular fossa and/or internal mammary chain may be considered on an individualized basis (see chapter 10).

Partial breast irradiation There have been several reports demonstrating promising results with the

use of partial breast irradiation, a potentially more convenient option for patients than the extended course of postoperartive radiotherapy.

Additional options are now available to shorten the radiotherapy treatment time to 1 to 5 days (accelerated) and to focus an increased dose of radiation on just the breast tissue around the excision cavity (partial breast). Current accelerated partial breast irradiation (APBI) approaches include interstitial brachytherapy, intracavitary (balloon) brachytherapy, and accelerated external beam (three-dimensional conformal) radiotherapy. Intraoperative radiotherapy is even shorter, with the entire treatment given as a single dose delivered immediately after surgery. Each approach has benefits and limitations.

Ongoing randomized trials will shape how APBI is utilized in routine clinical practice. Some of the more important outcomes from these trials will be local toxicity, local and regional recurrence, and overall survival. If APBI is ultimately demonstrated to be as safe and effective as whole-breast radiotherapy, breast conservation may become an even more appealing choice, and the overall impact of treatment may be further reduced for certain women with newly diagnosed breast cancer.

Mastectomy options

Patients who are not candidates for breast conservation or who are not interested in breast conservation are offered mastectomy. For patients who desire immediate reconstruction at the time of mastectomy, a skin-sparing approach is recommended, provided it is oncologically safe. In most instances, the mastectomy can be performed through a circumareolar incision, where the nipple-areolar complex (NAC) is excised in continuity with the breast tissue. If a biopsy has been performed, this skin should also be excised with the mastectomy specimen. There have been reports in the literature in which the NAC has been spared during the course of a skin-sparing mastectomy. This concept awaits further study and is not considered standard of care.

MEDICAL TREATMENT

Medical management of local disease depends on clinical and pathologic staging. Systemic therapy is indicated only for invasive (infiltrating) breast cancers.

In the past, systemic therapy was not offered to patients with stage I disease (tumors up to 2.0 cm). However, adjuvant chemotherapy and hormonal therapy have been shown to improve disease free and overall survival in selected patients with node-negative disease.

The sequence of systemic therapy and radiation therapy for patients treated with breast-conserving therapy has been the subject of considerable debate. Although concurrent CMF (cyclophosphamide, metho-trexate, fluorouracil [5-FU]) and radiation therapy have been used with accetable toxicity, the concurrent use of chemoradiation therapy has fallen out of favor due to reports of enhanced toxicities. Delaying chemotherapy for 6 to 8 weeks of radiation therapy does not appear to negatively impact systemic disease or survival. Recent studies do not demonstrate a compromise in local control if radiation is delayed until chemotherapy is complete. Currently, the majority of patients receiving chemotherapy and radiation therapy are treated with chemotherapy prior to radiation therapy.

For patients receiving tamoxifen or other hormonal agents, there had been considerable controversy regarding whether the hormonal agents should be administered during or after radiation therapy. Theoretically, tamoxifen may place cells in a resting state, making them less radiosensitive. Three retrospective studies, conducted independently but published together, all reached a similar conclusion: The timing of therapy had no impact on local relapse rates. Additionally, no significant difference was found in time to any event, metastasis, or death whether subsequent therapy was radiotherapy first or chemotherapy first among patients with breast conservation.

Treatment regimens

Multiagent therapy with CMF, CMF and prednisone (CMFP), sequential methotrexate and 5-FU (MF), and Adriamycin (doxorubicin) and cyclophosphamide (AC) has been used in patients with node-negative disease (Table 2). Hormonal therapy with tamoxifen (20 mg PO every day for 5years) has been shown to be of value in women ≥ 50 years of age with estrogen and/or progesterone receptor positive tumors. (See chapter 10 for further discussion about tamoxifen and the ATAC trial [Arimidex and Tamoxifen Alone or in Combination] as well as for adjuvant chemotherapy regimens for node-positive breast cancer.)

Taxanes (ie, paclitaxel and docetaxel [Taxotere]) are now routinely used in the adjuvant therapy for node-positive breast cancer. The role of taxanes in node-negative disease is still evolving.

Node-negative tumors < 1.0 cm The reduction in the odds of recurrence and death with adjuvant therapy is similar in estrogen receptor-negative and -[node]-negative patients. Therefore, patients who have the lowest risk of recurrence are least likely to benefit from systemic treatment when the attendant risks of -treatment are considered. None of the reported trials in node-negative breast cancer included women with tumors < 1.0 cm, and because of the low risk of recurrence (≤ 10%) in this group, systemic adjuvant therapy is not used routinely. Recent results from the NSABP in this group of patients are provocative in suggesting a potential benefit from systemic therapy.

In this validation study, the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen receptor-positive breast cancer was tested using a reverse transcriptase (RT)-PCR assay of 21 prospectively selected genes (16 cancer-related genes and 5 reference genes) in paraffin-embedded tumor tissue. The levels of expression of the 21 genes were used in a prospectively defined algorithm to calculate a recurrence score and to determine a risk group for each patient.

The proportions of patients categorized as having a low, intermediate, or high risk by the RT-PCR assay were 51%, 22%, and 27%, respectively. The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low, intermediate, and high-risk groups were 6.8%, 14.3%, and 30.5%, respectively. The rate in the low-risk group was significantly lower than that in the high-risk group (P < .001). In a multivariate Cox model, the recurrence score provided significant predictive power that was independent of age and tumor size (P < .001). The recurrence score was also predictive of overall survival (P < .001) and could be used as a continuous function to predict distant recurrence in individual patients.

Node-negative tumors ≥ 1.0 cm The selection of a specific treatment program and the characteristics that predict risk of recurrence and death in women with node-negative breast cancer require further delineation and clarification in clinical trials. At present, women with tumors ≥ 1.0 cm who have poor histologic or nuclear differentiation, negative estrogen receptors, a high S-phase percentage, or high Ki-67 can be considered appropriate candidates for adjuvant systemic therapy.

An update of the NSABP B-20 trial indicated a significant advantage in the estrogen receptor-positive, node-negative population when chemotherapy with CMF or sequential MF is added to tamoxifen in the adjuvant setting. Patients receiving CMF plus tamoxifen appeared to derive the greatest benefit. Benefits with respect to both disease-free and overall survival have been reported for patients given chemotherapy and tamoxifen.

Chemotherapy and ovarian function suppression are both effective adjuvant therapies for patients with early-stage breast cancer. The efficacy of their sequential combination was investigated by the International Breast Cancer Study Group (IBCSG) Trial VIII. This study randomized more than 1,000 pre and perimenopausal women with lymph node-negative breast cancer to receive either goserelin (Zoladex) for 24 months (n = 346), 6 courses of "classic" CMF chemotherapy (n = 360), or 6 courses of classic CMF followed by 18 months of goserelin (CMF then goserelin; n = 357). The primary outcome was disease-free survival.

In this study, patients with estrogen receptor-negative tumors achieved better 5-year disease-free survival rates if they received CMF (84% and 88% for CMF and CMF then goserelin, respectively) than if they received goserelin alone (73%). However, for patients with estrogen receptor-positive disease, chemotherapy alone and goserelin alone provided similar outcomes (81% 5-year disease-free survival rates for both treatment groups), whereas sequential therapy provided a statistically nonsignificant improvement compared with either modality alone.


 

Follow-up of long-term survivors

There is no consensus among oncologists as to the optimal follow-up routine for long-term breast cancer survivors. Based on guidelines from the National Comprehensive Cancer Network (NCCN), patients with stage 0 breast cancer should undergo a medical history and physical examination every 6 months for 5 years and then annually thereafter; mammography should be performed every year. Patients with stage I breast cancer should undergo a medical history and physical examination every 4 to 6 months for 5 years and then annually thereafter. In stage I patients, mammography should be performed every 6 months in the ipsilateral breast after radiation therapy following breast-conserving surgery and then annually thereafter, including the contralateral breast; if mastectomy was performed, mammography should be performed annually in the contralateral breast. Women receiving tamoxifen should undergo pelvic examination every 12 months if the uterus is present. All other follow-up evaluations are dictated by the development of symptoms.

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Chlebowski RT, Blackburn GL, Thomson CA, et al: Dietary fat reduction and breast cancer outcome: Interim efficacy results from the Women's Intervention Nutrition Study. J Natl Cancer Inst 98:1767–1776, 2006.

Fyles AW, McCready DR, Manchul LA, et al: Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 351:963–970, 2004.

Hughes KS, Schnaper LA, Berry D, et al: Cancer and Leukemia Group B; Radiation Therapy Oncology Group; Eastern Cooperative Oncology Group: Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 351:971–977, 2004.

Kerlikowske K, Molinaro A, Cha I, et al: Characteristics associated with recurrence among women with ductal carcinoma in situ treated by lumpectomy. J Natl Cancer Inst 95:1692–1702, 2003.

King TA, Fey JV, Van Zee KJ, et al: A prospective analysis of the effect of blue-dye volume on sentinel lymph node mapping success and incidence of allergic reaction in patients with breast cancer. Ann Surg Oncol 11:535–541, 2004.

Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826, 2004.

Vinh-Hung V, Verschraegen C: Breast-conserving surgery with or without radiotherapy: Pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 96:115–121, 2004.

Voogd AC, Nielsen M, Peterse JL, et al: Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: Pooled results of two large European randomized trials. J Clin Oncol 19:1688–1697, 2001.