Stages 0 and I Breast Cancer

Overview 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 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 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 seen on a 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 of 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 shifted to individuals in their 50s. The incidence of LCIS decreases in women who are in their 60s to 80s. The age at which the peak incidence of LCIS occurs may be related to the use of hormone replacement therapy. It is also possible that use of hormone replacement therapy 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 separate mammographic abnormality or palpable mass. Risk of invasive cancer Approximately 20% to 25% of women 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 duct lobular apparatus, and the disease tends to be multifocal, multicentric, and bilateral. Subsequently, other types of LCIS have also been described. One of these, pleomorphic LCIS, tends to be associated with infiltrating lobular carcinoma, and its cytologic features are similar to those of intermediate- or high-grade DCIS. Pleomorphic LCIS may be more aggressive and more likely to progress 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, use of tamoxifen, or bilateral prophylactic total mastectomy with or without reconstruction. At present, the decision regarding a given treatment will depend upon the patient’s individual risk profile for DCIS or invasive breast cancer, determined after careful counseling. In the future, treatment decisions may be based upon an analysis of a series of molecular markers, which can separate 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 2012, an estimated 63,300 new cases of in situ breast cancer were estimated to occur among women, with approximately 85% being DCIS. 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. Parikh et al compared the clinicopathologic features and long-term outcomes from women with DCIS vs DCIS with microinvasion (DCISM) treated with breast conservation, to assess the impact of microinvasion. They concluded that natural history of DCISM closely resembles that of DCIS. The incidence of axillary metastasis in DCISM appears to be small (less than 3%) and does not appear to correlate with outcomes. Furthermore, the incidence of locoregional and distant failures in DCISM is low. Thus, microinvasion should not be the sole criterion for more aggressive treatment. 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. Kuhl et al investigated the sensitivity of mammography vs magnetic resonance imaging (MRI) in detecting DCIS and compared the biological profiles of abnormalities detected by each method. Over a 5-year study period, 198 women had a pathologic diagnosis of pure DCIS without associated invasive breast cancer or microinvasion. In all, 167 of these women underwent both imaging tests preoperatively; 93 (56%) of these cases were diagnosed by mammography, and 153 (92%) were diagnosed by MRI (P < .001). The sensitivity of mammography decreased with nuclear grade; it was highest in patients with low-grade DCIS and lowest in cases of high-grade DCIS. The sensitivity of MRI was superior to that of mammography across all DCIS subtypes. In addition, sensitivity increased with nuclear grade of DCIS; it was lowest in low-grade cases (80%) and highest in high-grade cases (98%), independent of the presence or absence of necrosis. 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 they generally present in the same quadrant within 10 years of the DCIS diagnosis. 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 (eg, solid, cribriform, 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 about 1% to 2%, neither sentinel node nor axillary dissection is 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. The extent of surgical margins remains controversial. The American Society of Breast Surgeons has published a position paper which states that if inked margins are negative and are greater than or equal to 1 mm, no reexcision is recommended. If the margins are close or focally involved, reexcision is not mandatory and is considered on a case-by-case basis. If tumor is on ink, reexcision is indicated. If the DCIS presented as microcalcifications, a mammogram is necessary to document complete excision of the microcalcifications prior to reexcision. Sentinel node biopsy. The sentinel lymph node is the first node in the draining lymphatic basin that receives primary lymph flow. Sentinel lymph node biopsy represents a minimally invasive way to determine whether the axilla is involved with disease. 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 handheld 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 DCIS that is so extensive as to require 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. For patients diagnosed with DCIS who have these associated factors and in patients who are scheduled for mastectomy, sentinel lymph node biopsy is a reasonable practice and should be included in the preoperative discussion. In the event that an occult invasive cancer within the mastectomy is found, a negative sentinel node would make it possible to avoid axillary dissection. Sentinel lymph node biopsy is discussed below and axillary node dissection following sentinel node biopsy is discussed further in the “Stage II Breast Cancer” chapter. Adjuvant radiation therapy. Retrospective series have analyzed data on patients with DCIS, as well as subsets of patients with early invasive cancer 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 that it 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 trial, the local recurrence rate at 8 years was reduced from 27% to 12% with postlumpectomy irradiation. Similar results have been reported by the European Organisation for Research and Treatment of Cancer (EORTC) 10853 trial, in which 1,010 women with DCIS were 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 15.8 years, almost one in three nonirradiated women developed a local recurrence after lumpectomy for DCIS and radiotherapy reduced this risk by a factor of 2. At 15 years, the local recurrence–free rate was 69% in the observation group and 82% in the radiotherapy group. The differences in local recurrence between the two study arms did not lead to differences in breast cancer–specific survival or overall survival. 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 Predictive 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 with and without radiation for DCIS. In some series, VNPI lacked discriminatory power for guiding further patient management. In studies performed by this group, the width of the excision margin apparently was 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. However, adjuvant radiotherapy was omitted in a single-arm, prospective study of patients with grade 1 or 2 DCIS having a mammographic extent < 2.5 cm and treated with wide excision with final margins ≥ 1 cm. This trial was closed early, because the number of local recurrences met the predetermined stopping rules. The 5-year rate of ipsilateral breast tumor recurrence was 12%. Thus, the benefit of radiotherapy is still seen in traditionally low-risk patients. Although there may be some patients for whom wide excision alone is appropriate therapy, no specific subgroup has been identified consistently in the available literature. 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 in older women with breast cancer. Both studies randomized patients, following lumpectomy and adjuvant hormonal therapy, to receive radiotherapy or observation. Both studies confirmed statistically significant improvements in local control with radiation therapy, 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 radiotherapy) following breast-conserving therapy. Hughes et al published a prospective, nonrandomized study on behalf of the Eastern Cooperative Oncology Group (ECOG), E5194, which tried to determine the risk of ipsilateral breast events in patients with DCIS treated with local excision without irradiation. Eligible patients were those with either low- or intermediate-grade DCIS measuring 2.5 cm or smaller, or high-grade DCIS measuring 1 cm or smaller who had microscopic margin widths of 3 mm or wider and no residual calcifications on postoperative mammograms. At 10-year follow-up, ipsilateral breast recurrence rates of DCIS for patients with low- or intermediate-grade DCIS was 15.4%, and for high-grade DCIS was 15.1%. Recurrence with invasive breast cancer occurred in 5.6% of patients with low- or intermediate-grade DCIS and in 9.8% of patients with high-grade DCIS. Goyal et al investigated the ipsilateral breast tumor recurrence (IBTR) in DCIS patients treated with brachytherapy in the MammoSite registry trial. A total of 194 patients with DCIS were treated, 70 of whom met criteria for the E5194 study. In contrast to the findings from E5194, the 5-year IBTR was lower at 0% and 5.3% for the low/intermediate grade (n = 41) and high-grade cohort (n = 29), respectively. The overall 5-year IBTR was 2%, with a median follow-up of 52.7 months. Thus, new methods for analyzing recurrence risk would be helpful in determining the need for adjuvant breast irradiation after wide excisions. Tissue samples were available from 49% of patients in the E-5194 study, and those samples were analyzed using a quantitiative multigene reverse transcriptase polymerase chain reaction (RT-PCR) assay. To provide more accurate and reproducible assessment of recurrence risk, Solin and colleagues performed the Oncotype DX assay on samples from 327 patients (49% of the parent study) in E5194. A new, prespecified DCIS Recurrence Score was designed to predict recurrence using an optimized gene-expression algorithm. The primary objective was to determine whether there was a significant association between the risk of an ipsilateral breast event (IBE) and the continuous DCIS Score in Cox models. A total of 46 patients had an IBE (defined as ipsilateral local recurrence of DCIS [n = 20] or invasive cancer [n = 26]). Median follow-up was 8.8 years. The 10-year IBE rates were 15.4% for low- or intermediate-grade DCIS and 15.1% for high-grade DCIS (as determined by central pathology review), and for invasive IBE, 5.6% and 9.8%, respectively. Continuous DCIS Score was significantly associated with IBE (hazard ratio [HR] = 2.34 per 50 units; 95% confidence interval [CI], 1.15–4.59; P = .02) when adjusted for tamoxifen use and with invasive IBE (HR = 3.73; CI, 1.34–9.82; P = .01). DCIS Score was significantly associated with outcome when evaluated by the prespecified risk groups. Similar results were observed with and without adjustment for tamoxifen use or for negative margin width. Features associated with IBE in multivariate models included menopausal status (HR = 0.49; 95% CI, 0.27–0.9; P = .02), tumor size (HR = 1.52 per 5 mm; 95% CI, 1.11–2.01; P = .01), and continuous DCIS Score (HR = 2.41; 95% CI, 1.15–4.89; P = .02). The authors concluded that the DCIS Score provides a new clinical tool for individualized selection of treatment for patients with DCIS. After breast-conserving surgery, radiotherapy is administered using tangential fields to the whole breast with a standard dose of 45 to 50 Gy delivered in daily fractions of 180 to 200 cGy. On the basis of extrapolation from data on the treatment of invasive breast cancer, a radiation boost to the tumor bed may be added to whole-breast treatment, particularly for women with close surgical margins, although the benefit of a boost in the management of DCIS is not established. Rakovitch et al conducted a pooled analysis of 1,895 cases of DCIS treated with BCT, in which 561 patients had received boost radiation. The cumulative 10-year rate of local recurrence was 13% for women who received boost radiation and 12% for those who did not (P = .3), and on multivariate analyses boost radiation was not associated with a lower risk of local recurrence (P = .25). Adjuvant trastuzumab therapy. Overexpression of HER2/neu is seen in more than 50% of cases of DCIS. It has been associated with high-risk disease (young age, estrogen receptor–negative status, high nuclear grade). NRG Oncology is conducting a clinical trial (NSABP B-43) in which patients with DCIS that is HER2/neu-positive who have undergone wide excision with negative surgical margins will be randomized to receive whole breast irradiation (WBI) alone vs WBI and two doses of trastuzumab (Herceptin) at weeks 1 and 4. Patients who are estrogen- and/or progesterone-positive will receive 5 years of hormone therapy. The goal of the study is to determine whether the addition of trastuzumab can prevent an IBTR. Adjuvant tamoxifen therapy. Adjuvant chemotherapy is not routinely employed for patients with DCIS. In the NSABP B-24 trial, 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 did 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, the benefit of tamoxifen was derived exclusively from patients with hormone receptor–positive disease. The pros and cons of tamoxifen should be discussed for the prevention of secondary breast cancers in women at high risk for breast cancer, such as women diagnosed with DCIS. Wapnir et al analyzed data from 2,612 women with primary DCIS who participated in the NSABP B-17 and B-24 trials for IBTR; patients were followed for a median of > 17 years. IBTR was a first failure in 490 patients (263 invasive, 227 noninvasive). The 15-year cumulative incidence of all such invasive recurrences was 19.4% for lumpectomy only, 8.9% for lumpectomy with WBI, 10% for lumpectomy with WBI plus placebo, and 8.5% for lumpectomy with WBI plus tamoxifen. Radiotherapy significantly reduced invasive IBTR. Tamoxifen conferred additional benefit in reducing invasive recurrences of this type. Women with invasive IBTRs had a nearly twofold greater mortality risk relative to those who did not; the effect was greater for patients who underwent lumpectomy followed by WBI than for those who underwent only lumpectomy. Overall mortality was low and primarily due to development of IBTR. The investigators concluded that occurrence of an invasive IBTR after DCIS, and particularly after radiotherapy, confers increased risk for subsequent mortality, as seen after an invasive index tumor. 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 or with only limited nodal involvement (N1mi). 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. Radiation and Surgical Treatment 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 Society of Surgical Oncology (SSO) and the American Society of Radiation Oncology (ASTRO), developed a consensus statement on margin width and risk of IBTR. They found that positive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a twofold increase in the risk of IBTR compared to negative margins, and this increased risk is not reduced by favorable biology, endocrine therapy, or a radiation boost. They also found that more widely clear margins than no ink on tumor do not significantly decrease the rate of IBTR. They concluded that the use of no ink on tumor, which was the guideline used in the NSABP trials, is the standard for an adequate margin in management of invasive cancer in the era of multidisciplinary therapy. The extent of axillary surgery also continues to evolve. Patients with early-stage breast cancer who have clinically node-negative disease have the option to undergo sentinel lymph node biopsy (SLNB) rather than axillary lymph node dissection (ALND). TABLE 1: Contraindications to breast conservation 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. No study has documented an improved local recurrence or IBTR rate with MRI presurgical screening. 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 IBTR has been reported to range from 0.5% to 2% per year, with long-term failure rates varying from 7% to 20%. Risk factors for IBTR 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 removal of the least amount of breast tissue possible. Earlier studies demonstrated that an extensive intraductal component was a risk factor for local relapse. In subsequent reports, however, when negative surgical margins were achieved, patients with an extensive intraductal component could 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 previously cited risk factors in predicting recurrence is unclear, and patients should not be denied breast conservation because of their presence. • Cosmetic considerations-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 the “Stage III and IV Breast Cancer” chapter for a 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. Such women may undergo bilateral reduction mammoplasty after the wide excision of the primary tumor site. 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. Unfortunately, the follow-up mammograms will be more difficult to interpret, owing to scarring and effects of radiotherapy. 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 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 subareolar lesions do not necessarily need to have the nipple-areolar complex sacrificed, as long as negative surgical margins can be achieved. If the complex is not removed, however, the remaining breast tissue and overlying skin may or may not 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. To date, studies 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. Smith et al demonstrated high rates of second primary tumors in the ipsilateral breast. This study from Yale suggested 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 indicated 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 routine ALND in breast cancer is primarily for the management of clinically node-positive disease and is discussed in subsequent chapters. For a patient with a clinically negative axilla, SLNB has replaced ALND. Patients whose SLNB is negative may not require a complete node dissection, as the risk of an axillary recurrence is extremely low. ALMANAC is a multicenter randomized trial (UK National Cancer Research Network Trial ID 843) of 1,031 patients assigned to SLNB (n = 515) or standard ALND (n = 516). Mansel reported the primary outcome measures, which were arm and shoulder morbidity and quality of life. Drain usage, length of hospital stay, and resumption of normal activities after surgery were all highly significantly better in the SLNB group. In addition, patient-recorded quality of life and arm functioning scores were also significantly better, with no increase in anxiety levels in the sentinel node group. The authors conclude that SNLB is the treatment of choice for patients who have early-stage breast cancer and clinically negative nodes. Many institutions are using immunohistochemistry (IHC) to evaluate 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 isolated tumor cells are seen but no cluster is greater than 0.2 mm, the node is staged as pN0 (i+). If the focus of metastatic disease in the node is > 0.2 mm but < 2 mm, the node is staged as pN1mi. Traditionally, women with metastatic disease identified in the sentinel node will have undergone a completion ALND. This practice may be unnecessary for certain groups of women with early-stage breast cancer, however. Giuliano et al reported on approximately 900 patients with invasive T1-T2 breast cancer with a clinically negative axillary exam who were treated with breast-conserving surgery, adjuvant tangential WBI, and SLNB. All of the patients in the study had negative surgical margins and positive SLNBs. Patients were excluded if they had three or more sentinel nodes, matted nodes, gross extranodal disease, or neoadjuvant hormonal therapy or chemotherapy. Patients were randomized to undergo completion ALND (n = 445) or no further surgery (n = 446). The patients received appropriate systemic therapy, either chemotherapy or hormone therapy, or both. At a median follow-up of 6.3 years, the 5-year disease-free survival (82.2% vs 83.9%) and overall survival (91.8% vs 92.5%) were similar in the ALND and SLND alone groups. This study suggests that patients who are treated with breast-conserving surgery, WBI, and systemic therapy may not require a completion ALND when there is minimal metastatic disease identified in the sentinel node(s). This does not apply to patients undergoing mastectomy or for patients who have had breast-conserving surgery but will be receiving partial breast radiation. Patients who may not be candidates for SLNB are women who are pregnant or breastfeeding or who have had prior irradiation. A prior excisional biopsy does not preclude the use of lymphatic mapping and SLNB. It has been suggested that SLNB 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. The success rate for identifying the sentinel node may 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 technetium-99m sulfur colloid are used together. When blue dye is used alone, the success rate is 83%, and when technetium-99m sulfur colloid is used alone, the success rate is 94%. Results from a multi-institution practice have demonstrated that SLNB using dual-agent injection provides maximal sensitivity. In the study, reported by McMasters et al in 2000 in the Journal of Clinical Oncology, 806 patients were enrolled by 99 surgeons for SLNB 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-agent vs dual-agent injection. However, the false-negative rate was 11.8% for single-agent injections vs 5.8% for dual-agent injections (P = .05). The sensitivity and specificity of SLNB 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 for which 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 SLNB is normal do not require a complete node dissection, because the risk of an axillary recurrence is extremely low. 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. A meta-analysis demonstrated a substantially reduced local relapse rate and a small but statistically significant decrease in breast cancer mortality with use of radiation following breast-conserving surgery. There has been controversy regarding the role of radiation therapy in women over the age of 70 years with small breast cancers. The CALGB 9343 trial enrolled women over age 70 with clinically node-negative disease, who had undergone lumpectomy with a clear margin (1-cm negative margin), had a tumor size of 2 cm or less, and were estrogen receptor–positive or of indeterminate status. These women were randomized to either tamoxifen or tamoxifen plus radiation and followed for a median of 12 years. Radiation therapy was found to have an impact on breast tumor recurrence, with 6 events occurring in the 317 women who received tamoxifen plus radiation, compared with 27 events in 319 women who did not receive radiation (2% vs 9%, P < .001). However, there were no benefits in terms of ultimate mastectomy (2% with radiation vs 4% without, P = .1779), axillary recurrence (0% with vs 3% without radiation), the frequency of second primary cancers (12% vs 9%, P = .7268), or overall survival at 10 years (33% of patients in each treatment arm had died at 10 years, P = .845). To date, approximately 50% of the women are still alive, 3% have died from breast cancer, and 46% have died from other causes. It is notable that approximately 50% of women who were over 70 years of age upon enrollment in this study are still alive 12 years later. The investigators concluded that in older women the benefits of radiation after lumpectomy are small and that omitting radiation in women over 70 years of age with clinical stage I breast cancer is a reasonable alternative. Significance of tumor biology on local control The Danish Breast Cancer Cooperative Group reported on a 20-year follow-up of the DBCG-82TM trial: A series of 793 patients with invasive breast cancer treated with lumpectomy and radiation therapy were stratified based on receptor status: patients in the luminal A group were estrogen receptor–positive or progesterone receptor–positive and HER2-negative; those in the luminal B group were estrogen receptor–negative, progesterone receptor–negative, and HER2-positive; those in the HER2 group were estrogen receptor–negative and progesterone receptor–negative and HER2-positive; and the basal group was estrogen receptor–negative, progesterone receptor–negative, and HER2-negative. Over a median follow-up of 70 months, the 5-year rate of IBTR was 1.8% for the luminal A group, 1.5% for the luminal B group, 8.4% for HER2 group, and 7.5% for basal subtypes. Voduc et al investigated the rate of local and regional relapse in 2,985 patients stratified by molecular subtype. With a median follow-up of 12 years, they found that after breast-conserving surgery plus RT, patients with luminal A tumors had the most favorable prognosis, with local relapse and regional relapse rates of only 8% and 3% at 10 years, respectively. HER2-enriched and basal-like groups exhibited the highest rates of local relapse (21% and 14%, respectively) and regional relapse (16% and 14%, respectively). Kiess et al reported on a series of 197 women with early-stage breast cancer with HER2-positive disease. In this cohort, 70 women received RT alone while 102 received RT plus trastuzumab (given in standard fashion, ie, 1 year of treatment). They found that the 3-year locoregional recurrence–free survival rate was 90% with RT alone compared with 99% in those treated with RT plus trastuzumab. Finally, Abdulkarim et al reported a higher rate of local relapse among T1/T2 node-negative mastectomy patients treated without radiation who had triple-negative disease, compared with a similar node-negative cohort treated with breast-conserving surgery and radiation; this emphasizes the point that patients with triple-negative breast cancers do not necessarily fare better with mastectomy. These results may be useful in counseling patients about their outcomes after breast-conserving therapy. 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 4% absolute reduction in local relapse was seen with the use of the radiation boost (6.2% vs 10.2% at 10 years). 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 the “Stage II Breast Cancer” chapter). Accelerated whole breast irradiation (AWBI). In contrast to conventional assumptions, the fractionation sensitivity for breast tumors may be much lower than expected; this allows for increasing the daily dose of radiation and shortening the overall treatment time. Based on this information, the Royal Marsden Hospital and the Gloucestershire Oncology Centre collaborated in a randomized clinical trial to evaluate the relative toxicity and efficacy of different whole-breast fractionation schemes. A total of 1,410 women were randomized to one of three arms: 50 Gy in 25 fractions over 5 weeks; 39 Gy in 13 fractions (3 Gy/fx) over 5 weeks; 42.9 Gy in 13 fractions (3.3 Gy/fx) over 5 weeks. The primary and secondary endpoints were late breast changes and local control. The 39 Gy arm was less likely to develop late radiation change compared to both 42.9 Gy and 50 Gy, but also had worse local control than the 42.9 Gy arm. Interestingly, the 42.9 Gy arm was not significantly different from the 50 Gy arm for both development of any late radiation change and local control. A National Cancer Institute of Canada trial randomized 1,234 patients (1993–1996) with T1 and T2 tumors with negative margins and pathologically negative nodes (on level 1 and 2 dissection) to 50 Gy in 25 fractions (2 Gy/fx) over a period of 35 days or 42.5 Gy in 16 fractions (2.66 Gy/fx) over 22 days. With a median follow-up of 69 months, local recurrence–free survival was equal (97.2% vs 96.8%), and there was no difference in overall and disease-free survival. Cosmesis was identical, with excellent or good scores at 3 and 5 years in 77% of patients in both groups. Toxicities were also comparable. A major limitation of the Canadian study is the lack of a standardized lumpectomy boost, which has been shown to significantly improve local control. The patients eligible for the study had low risk for disease recurrence, limiting the general scope of the results. Whelan et al updated the 15-year Canadian experience with hypofractioned WBI. The risk of local recurrence at 10 years was 6.7% among the 612 women assigned to standard irradiation vs 6.2% among the 622 women assigned to the hypofractioned regimen. They concluded that 10 years after treatment, accelerated hypofractionated WBI was not inferior to standard radiation treatment. The American Society for Radiation Oncology (ASTRO) convened a task force to formulate evidence-based guidelines on WBI fractionation. The task force conducted a systematic review of the literature, supplemented by the expertise and clinical experience of the task force members, to provide the rationale for the recommendations listed below. Trials that met inclusion criteria for the review were six randomized clinical trials comparing AWBI vs WBI, two randomized clinical trials comparing AWBI vs APBI, two randomized clinical trials comparing AWBI vs no irradiation, one randomized trial of AWBI alone with or without a boost to the tumor bed, and 34 nonrandomized clinical studies. After reviewing these studies, the task force reported that there was evidence to support the equivalence of AWBI and WBI for patients who satisfy all of the following criteria: • Age 50 years or older • Pathologic stage T1-2 N0 treated with breast-conserving surgery • Not treated with systemic chemotherapy • Within the breast along the central axis, minimum dose no less than 93% and maximum dose no greater than 107% of the prescription dose (± 7%) (as calculated with 2-dimensional treatment planning without heterogeneity corrections) • Patients should also be otherwise suitable for breast-conserving therapy in regard to standard selection rules (ie, not pregnant, no history of certain collagen-vascular diseases, no evidence of multicentric disease, no prior radiotherapy to the breast). For patients who do not satisfy all of these criteria, the task force could not reach consensus and chose not to render a recommendation either for or against AWBI in this setting. They did note, however, that their guideline should not prohibit or oppose the use of AWBI for patients not meeting all the criteria listed above. No consensus could be given, owing to the relative lack of evidence. Accelerated partial breast irradiation. Several reports have demonstrated promising results of partial breast irradiation, a potentially more convenient option for patients than the extended course of postoperative radiotherapy. Additional options are now available to shorten the radiotherapy treatment time to 1 to 5 days (accelerated irradiation) and to focus an increased dose of radiation on just the breast tissue around the excision cavity (partial breast irradiation). Current accelerated partial breast irradiation (APBI) approaches include interstitial brachytherapy, intracavitary (balloon) brachytherapy, and accelerated external beam (three-dimensional conformal) radiotherapy. Intraoperative radiotherapy time 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 WBI, 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. ASTRO convened a task force to formulate clinically useful evidence-based guidelines on APBI. A systematic review of the literature, which, supplemented by the expertise and clinical experience of the task force members, provided the rationale for their recommendations. After conducting a literature review, the panel identified four published randomized clinical trials and 38 prospective single-arm studies involving APBI. The task force reported that there was evidence to support use of APBI outside the realm of a clinical trial for patients who satisfy all of the following criteria: age ≥ 60 years; ≤ 2 cm of invasive ductal carcinoma, pN0; ≥ 2 mm margins; unicentric disease, without lymphovascular invasion; and estrogen receptor positivity. They also formed recommendations for a “cautionary” patient group and an “unsuitable” group for treatment with APBI outside of a clinical trial. Intraoperative radiation therapy (IORT) is given as a single dose directly to the tumor bed. Two large studies suggest that IORT offers about the same overall survival rates as whole-breast external beam radiation therapy (WBRT) for certain women diagnosed with early-stage breast cancer. TARGIT-A randomized more than 3,400 women > 45 years old diagnosed with early-stage breast cancer and scheduled for a lumpectomy to have either IORT or WBRT. Of the women randomized to IORT, 15.2% had to have additional WBRT after surgery because the final pathology showed more advanced characteristics than expected. At approximately 5 years of follow-up, the investigators found that both radiation techniques yielded about the same breast cancer survival rates: 97.4% for IORT vs 98.1% for WBRT. Women randomized to IORT had more in-breast recurrence than those with WBRT (3.3% vs 1.3%; P = .042). They had fewer skin toxicities than women treated with WBRT. The TARGIT-A study investigators concluded that IORT is a good option for certain women diagnosed with early-stage breast cancer. In the smaller ELIOT study, 1,305 women 48 to 75 years of age and diagnosed with early-stage breast cancer no larger than 2.5 cm were randomly assigned to treatment with IORT vs WBRT. After about 6 years of follow-up, the investigators found results that were similar to TARGIT-A results. While these two studies suggest that overall survival is similar in the short-term for IORT, the studies raise serious questions about how effective IORT is at reducing in-breast recurrences. Clearly, longer follow-up is needed. More research also needs to be done so to know exactly who can safely get IORT. Mastectomy options. Data accruing in the literature suggest that nipple-sparing mastectomy is oncologically safe and can be utilized in select cases of skin-sparing mastectomy. This surgical procedure can be considered in patients who will be undergoing mastectomy and immediate reconstruction. During the course of the surgery, the retroareolar tissue is removed and sent for frozen-section analysis. If the tissue sent for frozen section is negative, the nipple-areolar complex (NAC) can be spared. If the final pathology is positive, the NAC can be removed at a subsequent surgery. Factors associated with tumor extension to the NAC are subareolar tumor location, multicentricity, tumor size, and nodal positivity. The rate of complications may be higher with this technique, owing to partial loss of the NAC caused by impaired blood supply. 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 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, methotrexate, fluorouracil [5-FU]) and radiation therapy have been used with acceptable 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. It is important that the patient receive radiation therapy in a timely manner, however. 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, reached a similar conclusion about the timing of therapy, namely that it 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. TABLE 2: Adjuvant chemotherapy regimens for node-negative breast cancer Treatment regimens Multiagent therapy with CMF, CMFP (CMF and prednisone), MFL (sequential methotrexate and 5-FU), AC (Adriamycin [doxorubicin] and cyclophosphamide), and taxanes (paclitaxel, docetaxel [Taxotere]) has been used in patients with node-negative disease (Table 2). Hormonal therapy with tamoxifen (20 mg PO every day for 5 years) has been shown to be of value in both pre- and postmenopausal women with hormone receptor–positive breast cancer. (See “Stage II Breast Cancer” chapter for further discussion about tamoxifen and the ATAC (Arimidex and Tamoxifen Alone or in Combination) and aTTom (Adjuvant Tamoxifen To Offer More?) trials, as well as for adjuvant chemotherapy regimens for node-positive breast cancer.) Node-negative tumors < 1 cm. Patients who have the lowest risk of recurrence are least likely to benefit from systemic treatment when the risks of treatment are considered. None of the reported trials in node-negative breast cancer included women with tumors < 1 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 the Oncotype DX validation study, the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen receptor–positive breast cancer was tested using a 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 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 patieants. The Oncotype DX test has changed the treatment of breast cancer. It has shown that patients with low recurrence scores do not derive benefit from chemotherapy in addition to hormonal therapy, and therefore chemotherapy is omitted from their systemic therapy. Likewise, it showed patients with high risk-recurrence scores derive the most benefit from chemotherapy in addition to hormonal therapy, and therefore these patients are treated with chemotherapy followed by endocrine therapy. At this time, it is unclear whether patients with intermediate-risk recurrence scores benefit from chemotherapy in addition to endocrine therapy, but the recently completed TailoRx/PACTT-1 study is anticipated to provide an answer to this question. Node-negative tumors ≥ 1 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 cm who have poor histologic or nuclear differentiation, negative estrogen receptors, a high-risk Oncotype DX recurrence score, a high S-phase percentage, or a high Ki-67 level 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%). For patients with estrogen receptor–positive disease, however, chemotherapy alone and goserelin alone provided similar outcomes (5-year disease-free survival rates of 81% 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, 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. Thereafter, it can be done annually. 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. Lifestyle Modifications The Women’s Intervention Nutrition Study tested the effect of a dietary intervention in women with resected, early-stage breast cancer receiving conventional cancer management. Interim results showed that reduced dietary fat intake, with modest influence on body weight, may improve relapse-free survival. In all, 2,437 women were randomly assigned to a dietary intervention (n = 975) or a control (n = 1,462) group. After a median follow-up of 60 months, dietary fat intake was lower in the intervention group than in the control group (33.3 vs 51.3 fat grams/day at 12 months, respectively), corresponding to a statistically significant (P = .005), 6-pound-lower mean body weight in the intervention group. A total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) have been reported in the dietary group (9.8%) and in the control group (12.4%). The HR of relapse events in the intervention group compared with the control group was 0.76. Kwan et al assessed the association of alcohol consumption on breast cancer prognosis in the Life After Cancer Epidemiology (LACE) study. Included in the study were 1,897 early-stage breast cancer patients between 18 and 70 years of age, who completed treatment except for adjuvant hormonal therapy and were free of recurrence. Alcohol consumption was assessed on average 2 years after breast cancer diagnosis. A total of 51% of the participants were considered drinkers (> 0.5 g/d of alcohol), and the majority drank wine (89%). With a median follow-up of 7.4 years, participants who consumed ≥ 6 grams of alcohol per day were found to have an increased risk of both breast cancer recurrence (HR, 1.35; 95% CI, 1–1.83) and risk of death from breast cancer (HR, 1.51; 95% CI, 1–2.29) compared with nondrinkers. Furthermore, the increased risk of recurrence appeared to be greater among postmenopausal (HR, 1.51; 95% CI, 1.05–2.19) and overweight and obese women (HR, 1.60; 95% CI, 1.08–2.38). However, there was no association found with all-cause death and there appeared to be a reduction in risk of non–breast-cancer death. 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