National Cancer Institute

Posted Date: Apr 27, 2014

Expert-reviewed information summary about the treatment of ductal carcinoma in situ, lobular carcinoma in situ, and invasive breast cancer.

Breast Cancer Treatment

General Information About Breast Cancer

This summary discusses only primary epithelial breast cancers. Rarely, the breast may be involved by other tumors such as lymphomas, sarcomas, or melanomas. (Refer to the PDQ summaries on Adult Hodgkin Lymphoma Treatment, Adult Soft Tissue Sarcoma Treatment, and Melanoma Treatment for more information.)

Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2014:

  • New cases: 232,670.
  • Deaths: 40,000.

Genetic Characteristics and Risk Factors

Several well-established factors have been associated with an increased risk of breast cancer, including family history, nulliparity, early menarche, advanced age, and a personal history of breast cancer (in situ or invasive).

Age-specific risk estimates are available to help counsel and design screening strategies for women with a family history of breast cancer. Of all women with breast cancer, 5% to 10% may have a germ-line mutation of the genes BRCA1 and BRCA2. Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry. The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%. Carriers with a history of breast cancer have an increased risk of contralateral disease that may be as great as 5% per year. Male carriers of BRCA2 mutations are also at increased risk for breast cancer.

Mutations in either the BRCA1 or BRCA2 gene also confer an increased risk of ovarian cancer. In addition, mutation carriers may be at increased risk of other primary cancers. Genetic testing is available to detect mutations in members of high-risk families. Such individuals should first be referred for counseling. (Refer to the PDQ summaries on Genetics of Breast and Ovarian Cancer; Breast Cancer Prevention; and Breast Cancer Screening for more information.)


Clinical trials have established that screening with mammography, with or without clinical breast examination, may decrease breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.)

Patient Evaluation

Patient management following initial suspicion of breast cancer generally includes confirmation of the diagnosis, evaluation of stage of disease, and selection of therapy. At the time the tumor tissue is surgically removed, estrogen receptor (ER) and progesterone receptor (PR) status should be determined.

Prognostic and Predictive Factors

Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by the following clinical and pathology features (based on conventional histology and immunohistochemistry):

  • The age and menopausal status of the patient.
  • The stage of the disease.
  • The histologic and nuclear grade of the primary tumor.
  • The ER and PR status of the tumor.
  • Human epidermal growth factor type 2 receptor (HER2/neu) overexpression.
  • Proliferative capacity of the tumor (e.g., Ki67).

Molecular profiling has led to classification of breast cancer into the following five distinct subtypes:

  • Basal-like.
  • HER2+.
  • Normal.
  • Luminal A.
  • Luminal B.

The use of molecular profiling in breast cancer includes the following:

  • ER and PR status testing.
  • HER2/neu receptor status testing.
  • Gene profile testing by microarray assay or reverse transcription-polymerase chain reaction (e.g., MammaPrint, Oncotype DX).

Although certain rare inherited mutations, such as those of BRCA1 and BRCA2, predispose women to develop breast cancer, prognostic data on BRCA1/BRCA2 mutation carriers who have developed breast cancer are conflicting; these women are at greater risk of developing contralateral breast cancer. Since criteria for menopausal status vary widely, some studies have substituted age older than 50 years as a surrogate for the postmenopausal state. Breast cancer is classified into a variety of histologic types, some of which have prognostic importance. For example, favorable histologic types include mucinous, medullary, and tubular carcinoma.

Diagnostics and Survival

Contralateral Disease

Pathologically, breast cancer can be a multicentric and bilateral disease. Bilateral disease is somewhat more common in patients with infiltrating lobular carcinoma. Patients who have breast cancer should have bilateral mammography at the time of diagnosis to rule out synchronous disease. The role of magnetic resonance imaging (MRI) in screening and follow-up continues to evolve. Having demonstrated an increased detection rate of mammographically occult disease, the selective use of MRI for additional screening is being used with increased frequency despite the absence of randomized, controlled data. Because only 25% of MRI-positive findings represent malignancy, pathologic confirmation prior to treatment action is recommended. Whether this increased detection rate will translate into improved treatment outcome is unknown. When BRCA1/BRCA2 mutation carriers were diagnosed at a young age, the risk of a contralateral breast cancer reached nearly 50% in the ensuing 25 years.

Patients should continue to have regular breast physical examinations and mammography to detect either recurrence in the ipsilateral breast in those patients treated with breast-conserving surgery or a second primary cancer in the contralateral breast. The risk of a primary breast cancer in the contralateral breast ranges from 3% to 10% at 10 years after diagnosis, although endocrine therapy decreases that risk. The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.

Hormone Replacement Therapy

The use of hormone replacement therapy (HRT) poses a dilemma for the rising numbers of breast cancer survivors, many of whom enter menopause prematurely as a result of therapy. HRT has generally not been used for women with a history of breast cancer because estrogen is a growth factor for most breast cancer cells in the laboratory; however, empiric data on the safety of HRT after breast cancer are limited.

Two randomized trials (including Regional Oncologic Center-Hormonal Replacement Therapy After Breast Cancer--Is It Safe [ROC-HABITS]) comparing HRT with no hormonal supplementation have been reported. The first trial included 345 evaluable breast cancer patients with menopausal symptoms and was terminated early because of an increased incidence of recurrences and new primaries in the HRT group (hazard ratio [HR], 3.5; 95% confidence interval [CI], 1.5–7.4).[Level of evidence: 1iiDii] In total, 26 women in the HRT group and 7 in the non-HRT group developed recurrences or new primaries. This study, however, was not double blinded, and it is possible that patients on HRT were monitored more closely.

Because of the results of the first trial, the second trial, which was conducted under a joint steering committee with the first, closed prematurely after the enrollment of 378 patients. With a median follow-up of 4.1 years, there were 11 recurrences in the hormone replacement group and 13 recurrences in the patients assigned to no hormone replacement (HR, 0.82; 95% CI, 0.35–1.9).[Level of evidence: 1iiDii]

The trials differed in several ways; however, until further data become available, decisions concerning the use of HRT in patients with breast cancer will have to be based on the results of these studies and on inferences from the impact of HRT use on breast cancer risk in other settings. A comprehensive intervention, including education, counseling, and nonhormonal drug therapy, has been shown to reduce menopausal symptoms and to improve sexual functioning in breast cancer survivors.[Level of evidence: 1iiC] (Refer to the PDQ summaries on Hot Flashes and Night Sweats and Sexuality and Reproductive Issues for more information.)

Breast Reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction). Breast contour can be restored by the submuscular insertion of an artificial implant (saline-filled) or a rectus muscle or other flap. If a saline implant is used, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is replaced by a permanent implant. (Visit the FDA's Web site for more information on breast implants.) Rectus muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or if local disease recurs. Radiation therapy following reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.


Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared with routine physical examinations. Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected. Based on these data, some investigators recommend that acceptable follow-up be limited to physical examination and annual mammography for asymptomatic patients who complete treatment for stage I to stage III breast cancer. The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I to stage III breast cancer remain controversial.

Related Summaries

Other PDQ summaries containing information related to breast cancer include the following:

  • Breast Cancer Prevention
  • Breast Cancer Screening
  • Breast Cancer Treatment and Pregnancy
  • Genetics of Breast and Ovarian Cancer
  • Male Breast Cancer Treatment
  • Unusual Cancers of Childhood Treatment (breast cancer in children)

Cellular Classification of Breast Cancer

The following is a list of breast cancer histologic classifications. Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of all cases.

The following are tumor subtypes that occur in the breast but are not considered to be typical breast cancers:

  • Intraductal (in situ).
  • Invasive with predominant intraductal component.
  • Invasive, NOS.
  • Comedo.
  • Inflammatory.
  • Medullary with lymphocytic infiltrate.
  • Mucinous (colloid).
  • Papillary.
  • Scirrhous.
  • Tubular.
  • Other.
  • In situ.
  • Invasive with predominant in situ component.
  • Invasive.
  • Paget disease, NOS.
  • Paget disease with intraductal carcinoma.
  • Paget disease with invasive ductal carcinoma.
  • Undifferentiated carcinoma.

Stage Information for Breast Cancer

The American Joint Committee on Cancer (AJCC) staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but primarily according to tumor size, lymph node status, estrogen-receptor and progesterone-receptor levels in the tumor tissue, human epidermal growth factor receptor 2 (HER2/neu) status, menopausal status, and the general health of the patient.

Definitions of TNM

The AJCC has designated staging by TNM classification to define breast cancer. When this system was modified in 2002, some nodal categories that were previously considered stage II were reclassified as stage III. As a result of the stage migration phenomenon, survival by stage for case series classified by the new system will appear superior to those using the old system.

Posttreatment yp M classification. The M category for patients treated with neoadjuvant therapy is the category assigned in the clinical stage, prior to initiation of neoadjuvant therapy. Identification of distant metastases after the start of therapy in cases where pretherapy evaluation showed no metastases is considered progression of disease. If a patient was designated to have detectable distant metastases (M1) before chemotherapy, the patient will be designated as M1 throughout.

Ductal Carcinoma


Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to become invasive cancer, but estimates of the likelihood of this vary widely. Some people include DCIS in breast cancer statistics. The frequency of the diagnosis of DCIS has increased markedly in the United States since the widespread use of screening mammography. In 1998, DCIS accounted for about 18% of all newly diagnosed invasive plus noninvasive breast tumors in the United States.

Very few cases of DCIS present as a palpable mass; 80% are diagnosed by mammography alone. DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into several subtypes based primarily on architectural pattern: micropapillary, papillary, solid, cribriform, and comedo. Comedo-type DCIS consists of cells that appear cytologically malignant, with the presence of high-grade nuclei, pleomorphism, and abundant central luminal necrosis. Comedo-type DCIS appears to be more aggressive, with a higher probability of associated invasive ductal carcinoma.

Treatment Option Overview

Until recently, the customary treatment of DCIS was mastectomy. The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy following wide excision alone, and a 25% to 50% incidence of breast recurrence following limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma. The combined local and distant recurrence rate following mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation are available.

In view of the success of breast-conserving surgery combined with breast radiation for invasive carcinoma, this conservative approach was extended to the noninvasive entity. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins following excisional biopsy were randomized to either breast radiation (50 Gy) or to no further therapy.

Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or less. At the 12-year actuarial follow-up interval, the overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005). Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).[Level of evidence: 1iiDii] Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.

Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. At a median follow-up of 10.5 years, the overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001) with a similarly effective reduction of invasive (13% to 8%, P = .065) and noninvasive (14% to 7%, P = .001) recurrence rates.[Level of evidence: 1iiDii] In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy. In both of the studies reported here, the effect of radiation therapy was consistent across all assessed risk factors.

Given that lumpectomy and radiation therapy are generally applicable for most patients with DCIS, can a subset of patients be identified with such a low risk of local recurrence that postoperative radiation therapy can be omitted? To identify such a favorable group of patients, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.

The Van Nuys Prognostic Index, which combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification), was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy. Using this prognostic index, patients with favorable lesions, who received surgical excision alone, had a low recurrence rate (i.e., 2% with a median follow-up of 79 months). A subsequent analysis of these data was performed to determine the influence of margin width on local control. Patients whose excised lesions had margin widths 10 mm or larger in every direction had an extremely low probability of local recurrence with surgery alone (4% with a mean follow-up of 8 years). These reviews are retrospective, noncontrolled, and are subject to substantial selection bias. By contrast, no subset of patients was identified in the prospective NSABP trial that did not benefit from the addition of radiation therapy to lumpectomy in the management of DCIS.

To determine if tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial (NSABP-B-24) of 1,804 women. Patients were randomly assigned to lumpectomy, radiation therapy (50 Gy), and placebo versus lumpectomy, radiation therapy, and tamoxifen (20 mg/day for 5 years). Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured not larger than 1 cm, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases. Women in the tamoxifen group had fewer breast cancer events at 5 years than did those on a placebo (8.2% vs. 13.4%; P = .009).[Level of evidence: 1iDii] With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03). Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01). The benefit of tamoxifen extended to those patients with positive or uncertain margins. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

Treatment Options for Patients With DCIS

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with ductal breast carcinoma in situ. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Lobular Carcinoma


The term lobular carcinoma in situ (LCIS) is misleading. This lesion is more appropriately termed lobular neoplasia. Strictly speaking, it is not known to be a premalignant lesion, but rather a marker that identifies women at an increased risk for subsequent development of invasive breast cancer. This risk remains elevated even beyond 2 decades, and most of the subsequent cancers are ductal rather than lobular. LCIS is usually multicentric and is frequently bilateral. In a large, prospective series from the National Surgical Adjuvant Breast and Bowel Project (NSABP) with a 12-year follow-up of 182 women with LCIS that was managed with excisional biopsy alone, 26 women developed ipsilateral breast tumors (9 of the tumors were invasive). In addition, 14 women developed contralateral breast tumors (10 of the tumors were invasive).

Treatment Option Overview

Most women with LCIS have disease that can be managed without additional local therapy after biopsy. No evidence is available that re-excision to obtain clear margins is required. The use of tamoxifen has decreased the risk of developing breast cancer in women with LCIS and should be considered in the routine management of these women. The NSABP-P-1 trial of 13,388 high-risk women comparing tamoxifen to placebo demonstrated an overall 49% decrease in invasive breast cancer, with a mean follow-up of 47.7 months. Risk was reduced by 56% in the subset of 826 women with a history of LCIS, and the average annual hazard rate for invasive cancer fell from 12.99 per 1,000 women to 5.69 per 1,000 women. In women older than 50 years, this benefit was accompanied by an annual incidence of 1 to 2 per 1,000 women of endometrial cancer and thrombotic events. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

Bilateral prophylactic mastectomy is sometimes considered an alternative approach for women at high risk for breast cancer. Many breast surgeons, however, now consider this to be an overly aggressive approach. Axillary lymph node dissection is not necessary in the management of LCIS.

Treatment Options for Patients With LCIS

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with lobular breast carcinoma in situ. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage I, II, IIIA, and Operable IIIC Breast Cancer

Primary Therapy

Stage I, II, IIIA, and operable IIIC breast cancer often requires a multimodality approach to treatment. Irrespective of the eventual procedure selected, the diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures. In many cases, the diagnosis of breast carcinoma is made by core needle biopsy. After the presence of a malignancy is confirmed, treatment options should be discussed with the patient before a therapeutic procedure is selected. Estrogen-receptor (ER) and progesterone-receptor (PR) protein status and human epidermal growth factor receptor 2 (HER2/neu) status should be determined for the primary tumor. Additional pathologic characteristics, including grade and proliferative activity may also be of value.

Options for surgical management of the primary tumor include breast-conserving surgery plus radiation therapy, mastectomy plus reconstruction, and mastectomy alone. Surgical staging of the axilla should also be performed. Survival is equivalent with any of these options as documented in randomized prospective trials (including the European Organization for Research and Treatment of Cancer's trial [EORTC-10801]). Selection of a local therapeutic approach depends on the location and size of the lesion, analysis of the mammogram, breast size, and the patient’s attitude toward preserving the breast. The presence of multifocal disease in the breast or a history of collagen vascular disease are relative contraindications to breast-conserving therapy. A retrospective study of 753 patients who were divided into three groups based on receptor status (ER- or PR-positive; ER- and PR-negative but HER2/neu-positive; and ER-, PR-, and HER2/neu-negative [triple-negative]) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.

All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy. The rate of local recurrence in the breast with conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary is debatable.

Retrospective studies have shown the following examples of tumor characteristics to correlate with a greater likelihood of finding persistent tumor on re-excision:

  • Large tumors (T2 lesions).
  • Positive axillary nodes.
  • Tumors with an extensive intraductal component.
  • Palpable tumors.
  • Lobular histology.

Patients whose tumors have these characteristics may benefit from a more generous initial excision to avoid the need for a re-excision.

Radiation therapy (as part of breast-conserving local therapy) consists of postoperative external-beam radiation therapy (EBRT) to the entire breast with doses of 45 Gy to 50 Gy, in 1.8 Gy to 2.0 Gy daily fractions over a 5-week period. Shorter hypofractionation schemes achieve comparable results. A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years (P = .044),[Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001), respectively.[Level of evidence: 1iiDiii] If a boost is used, it can be delivered either by EBRT, generally with electrons, or by using an interstitial radioactive implant.

The age of the patient should not be a determining factor in the selection of breast-conserving treatment versus mastectomy. A study has shown that treatment with lumpectomy and radiation therapy in women 65 years and older produces survival and freedom-from-recurrence rates similar to those of women younger than 65 years. Whether young women with germ-line mutations or strong family histories are good candidates for breast-conserving therapy is not certain. Retrospective studies indicate no difference in local failure rates or overall survival (OS) when women with strong family histories are compared with similarly treated women without such histories.[Level of evidence: 3iiiDii] The group with a positive family history, however, does appear more likely to develop contralateral breast cancer within 5 years. This risk for contralateral tumors may be even greater in women who are positive for BRCA1 and BRCA2 mutations.[Level of evidence: 3iiiDii] Because of the available evidence indicating no difference in outcome, women with strong family histories should be considered candidates for breast-conserving treatment. For women with germ-line mutations in BRCA1 and BRCA2, further study of breast-conserving treatment is needed.

Breast-conserving surgery alone without radiation therapy has been compared with breast-conserving surgery followed by radiation therapy in six prospective randomized trials (including the National Surgical Adjuvant Breast and Bowel Project's trial [NSABP-B-06] and the Cancer and Leukemia Group B's trial [CLB-9343]). In two of these trials, all patients also received adjuvant tamoxifen. Every trial demonstrated a lower in-breast recurrence rate with radiation therapy, and this effect was present in all patient subgroups. In some groups, for example, women with receptor-positive small tumors and those older than 70 years, the absolute reduction in the rate of recurrence was small (<5%). The limited impact of radiation therapy in this group of women was also reported in a confirmatory observational study looking at in-breast control rates using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The impact of radiation therapy on local control was additionally clarified by showing that healthy women aged 70 to 79 years were most likely to benefit from radiation therapy (number needed to treat [NNT] to prevent one event = 21–22 patients) when compared with women aged 80 years or older or to those who have comorbidities (NNT = 61–125 patients). The administration of radiation therapy may be associated with short-term morbidity, inconvenience, and potential long-term complications.

The axillary lymph nodes should be staged to aid in determining prognosis and therapy. Sentinel lymph node (SLN) biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor, therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients. These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete axillary lymph node dissection (ALND).

A multicenter randomized phase III trial of 5,611 patients randomly assigned to either SLN plus ALND or to SLN resection alone with ALND only if the SLNs were positive showed no detectable difference in OS, disease-free survival (DFS), and regional control. OS was 91.8% versus 90.3% in the SLN plus ALND and SLN alone, respectively (P = .12).[Level of evidence: 1iiA]

Similarly, a single-center randomized trial of 532 patients with T1 carcinomas undergoing either SLN biopsy plus complete axillary dissection or SLN biopsy alone showed, after a median follow-up of 78 months, no difference in 5-year DFS (92.9% in the SLN biopsy without routine axillary dissection group vs. 88.9% in patients having axillary dissection irrespective of SLN findings, P = .1).[Level of evidence: 1iiDii]

The reported false-negative rates of SLN biopsy using axillary node dissection as the gold standard range from 0% to 15% with an average of 8.8%. The success rate varies with the surgeon’s experience and with the primary tumor characteristics. In general, studies have restricted the use of SLN biopsy to women with T1 and T2 disease, without evidence of multifocal involvement or clinically positive lymph nodes. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy. In a randomized trial of 1,031 women that compared SLN biopsy followed by axillary dissection when the SLN was positive with axillary dissection in all patients, quality of life at 1 year (as assessed by the frequency of patients experiencing a clinically significant deterioration in the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast scale) was superior in the SLN biopsy group (23% vs. 35% deteriorating in the SLN biopsy vs. axillary dissection groups, respectively; P = .001).[Level of evidence 1iiC] Arm function was also better in the SLN group. The NSABP-B-32 (NCT00003830) trial, a randomized study of 5,611 women, found the same results with respect to accuracy and technical success. Based on this body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer.

A multicenter, randomized clinical trial sought to determine whether ALND is required after an SLN biopsy reveals an SLN metastasis of breast cancer. This phase III noninferiority trial planned to randomly assign 1,900 women with clinical T1–T2 invasive breast cancer without palpable adenopathy and with one to two SLNs containing metastases identified by frozen section to undergo ALND versus no further axillary treatment. All patients underwent lumpectomy, tangential whole-breast irradiation, and appropriate systemic therapy, and OS was the primary endpoint. Because of enrollment challenges, a total of 891 women out of a target enrollment of 1,900 women were randomly assigned to one of the two treatment arms. At a median follow-up of 6.3 years, 5-year OS was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with ALND and 92.5% (95% CI, 90.0–95.1%) with SLN biopsy alone. The secondary endpoint of 5-year disease-free survival (DFS) was 82.2% (95% CI, 78.3%–86.3%) with ALND and 83.9% (95% CI, 80.2%–87.9%) with SLN biopsy alone.[Level of evidence: 1iiA] In a second, similarly designed trial, 929 women with breast tumors smaller than 5 cm and SLN involvement smaller than 2 mm were randomly assigned to receive or not receive axillary lymph node dissection. Patients without axillary dissection had fewer DFS events (hazard ratio [HR], 0.78; 95% CI, 0.55–1.11). No difference in OS was observed.[Level of evidence: 1iiA] On the basis of the results of these trials, the medical necessity of ALND after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation, radiation, and systemic therapy is called into question.

For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., 6–10 at least), while reducing morbidity from the procedure. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%. In another series, the incidence of axillary node relapse in patients with T1a tumors treated without ALND was 2%.[Level of evidence: 3iiiA] Because the axillary node status remains the most important predictor of outcome in breast cancer patients, insufficient evidence is available to recommend that lymph node staging can be omitted in most patients with invasive breast cancer.

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction). Breast contour can be restored by the submuscular insertion of an artificial implant (saline-filled) or a rectus muscle or other flap. If a saline implant is used, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. (Visit the FDA's Web site for more information on breast implants.) Rectus muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or if local disease recurs. Radiation therapy following reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.

Adjuvant Radiation Therapy

Radiation therapy is regularly employed after breast-conservation surgery. Radiation therapy also can be indicated for postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.

For women who are treated with breast-conserving surgery, the most common site of local recurrence is the conserved breast itself. The risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node-negative women. Thus, whole breast radiation therapy after breast-conserving surgery is recommended.

Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, in the 2005 Early Breast Cancer Trialists' Collaborative Group's (EBCTCG) update, when all relevant trials were combined, 15-year breast-cancer mortality was reduced from 35.9% to 30.5% in women receiving radiation therapy (absolute difference of 5.4%; 95% CI, 2.1%–8.7%; breast cancer death rate ratio 0.83; 95% CI, 0.75–0.91; P = .002). There was a similar effect on all-cause mortality.

Although adjuvant whole-breast radiation is standard treatment, no trials have addressed the role of regional lymph node radiation therapy in this setting. The National Cancer Institute of Canada's study (CAN-NCIC-MA20 [NCT00005957]) has closed, but until results are reported, decisions regarding the use of such therapy must rely on extrapolations from the postmastectomy setting and on knowledge of the local-regional recurrence rates following conservation therapy with axillary lymph node dissection for a given lesion.

Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for local-regional failure following mastectomy. Radiation therapy can decrease local-regional recurrence in this group, even among those patients who receive adjuvant chemotherapy. Patients at highest risk for local recurrence include those with four or more positive axillary nodes, grossly evident extracapsular nodal extension, large primary tumors, and very close or positive deep margins of resection of the primary tumor.

Patients with one to three involved nodes without any of the previously noted risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting has been unclear. The 2005 EBCTCG update indicates, however, that radiation therapy is beneficial, regardless of the number of lymph nodes involved.[Level of evidence: 1iiA] For women with node-positive disease postmastectomy and axillary clearance, radiation therapy reduced the 5-year local recurrence risk from 23% to 6% (absolute gain, 17%; 95% confidence interval [CI], 15.2%–18.8%). This translated into a significant (P = .002) reduction in breast cancer mortality, 54.7% versus 60.1% with an absolute gain of 5.4% (95% CI, 2.9%–7.9%). In subgroup analyses, the 5-year local recurrence rate was reduced by 12% (95% CI, 8.0%–16%) for women with one to three involved lymph nodes and by 14% (95% CI, 10%–18%) for women with four or more involved lymph nodes. In contrast, for women with node-negative disease, the absolute reduction in 5-year local recurrence was only 4% (P = .002; 95% CI, 1.8%–6.2%), and there was not a statistically significant reduction in 15-year breast cancer mortality in these patients (absolute gain, 1.0%; P > .1 95%; CI, -0.8%–2.8%). Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors, when axillary nodes were negative, the risk of isolated locoregional recurrence was low enough (7.1%) that routine locoregional radiation therapy was not warranted.

Late toxic effects of radiation therapy, though uncommon, can include radiation pneumonitis, cardiac events, arm edema, brachial plexopathy, and the risk of second malignancies. Such toxic effects can be minimized with current radiation delivery techniques and with careful delineation of the target volume.

In a retrospective analysis of 1,624 women treated with conservative surgery and adjuvant breast radiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months. The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular radiation field and to 8.8% when concurrent chemotherapy was administered. The incidence was only 1.3% in patients who received sequential chemotherapy.[Level of evidence: 3iii]

Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, had an association with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer. This was probably caused by the radiation received by the left myocardium.

Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left-breast radiation was used. Cardiac mortality decreased accordingly. At this time, cardiac mortality was also decreasing in the United States.

An analysis of SEER data from 1973 to 1989 reviewing deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.[Level of evidence: 3iB]

Lymphedema consequent to cancer management remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. Axillary radiation therapy can increase the risk of arm edema in patients who received axillary dissection from 2% to 10% with dissection alone to 13% to 18% with adjuvant radiation therapy. (Refer to the PDQ summary on Lymphedema for more information.)

Radiation injury to the brachial plexus following adjuvant nodal radiation therapy is a rare clinical entity for breast cancer patients. In a single-institution study using current radiation techniques, 449 breast cancer patients treated with postoperative radiation therapy to the breast and regional lymphatics were followed for 5.5 years to assess the rate of brachial plexus injury. The diagnosis of such injury was made clinically with computerized tomography to distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0% compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.

The rate of second malignancies following adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with the long-term risk at 0.2% at 10 years. One report suggests an increase in contralateral breast cancer for women younger than 45 years who have received chest wall radiation therapy after mastectomy. No increased risk of contralateral breast cancer occurs for women 45 years and older who receive radiation therapy. Techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible. In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.

Adjuvant Systemic Therapy

Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, estrogen and/or progesterone receptor–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression (e.g., triple negative, which is common in the basal-like tumors) nor hormone receptors are present, adjuvant therapy relies on chemotherapeutic regimens, which are often combined with experimental targeted approaches.

If ER status is used to select adjuvant treatment, the study should be performed in a well-established, skilled laboratory. Immunohistochemical assays appear to be at least as reliable as standard ligand-binding assays in predicting response to adjuvant endocrine therapy.

The role of bisphosphonates as part of adjuvant therapy for early stage breast cancer is unclear. The ABCSG-12 (NCT00295646) trial was a 2 × 2 factorial-design randomized trial that assigned 1,803 premenopausal patients with ER+ breast cancer to receive ovarian function suppression with goserelin and tamoxifen versus goserelin and anastrozole. These patients then underwent a second randomization to receive zoledronic acid (4 mg intravenously every 6 months) versus no zoledronic acid.[Level of evidence: 1iiA] There was no significant difference in DFS between the anastrozole and tamoxifen groups. However, the addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in a relative reduction of 36% in the risk of disease progression (HR, 0.64; P = .01) but did not significantly reduce the risk of death. Similar results were obtained in the trial (NCT00171340) in which 1,065 postmenopausal women received letrozole and were randomly assigned to receive zoledronic acid (4 mg intravenously every 6 months) immediately or only after the development of bone loss or fractures. Immediate administration of zoledronic acid resulted in a 34% improvement in DFS (HR, 0.66; 95% CI, 0.44–0.97, P = .035) but did not affect OS.[Level of evidence: 1iiA]

While bisphosphonates appear to improve DFS in a population with low-to-intermediate-risk breast cancer, this benefit does not appear to be seen in all patients with breast cancer. The AZURE trial was a randomized, phase III trial that assigned 3,660 patients with stage II or III breast cancer to receive chemotherapy and/or hormone therapy with or without zoledronic acid.[Level of evidence: 1iiA] At a median follow-up of 59 months, there was no significant benefit in the DFS in both groups (77% in each group; HR, 0.98; P = .79). OS was also similar, at 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted HR, 0.85; P = .07).

Based on the conflicting results of these trials, the exact role for bisphosphonates in adjuvant therapy for breast cancer is controversial. An ongoing phase III trial (NCT01077154) is examining the activity of the bone-modifying agent, denosumab, in stage II and III breast cancer.

Several phase III, clinical trials have addressed the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers.

In the HERceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial, which is the largest study (5,090 patients), trastuzumab was given every 3 weeks within 7 weeks of the completion of primary therapy that included, for most patients, an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, plus or minus locoregional radiation therapy.[Level of evidence: 1iiA] Also, 3,387 patients were enrolled in a comparison regimen of 1 year of trastuzumab (1,694 patients) versus observation (1,693 patients). Of these patients, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor (ER and PR)-negative disease. Patients who were treated with 1 year of trastuzumab experienced a 46% lower risk of a first event (hazard ratio [HR], 0.54; 95% CI, 0.43–0.67; P < .001), corresponding to an absolute DFS benefit of 8.4% at 2 years (95% CI, 2.1–14.8). The updated results at 23.5 months' follow-up showed an unadjusted HR for the risk of death with trastuzumab compared with observation of 0.66 (95% CI, 0.47–0.91; P = .0115), corresponding to an absolute OS benefit of 2.7%. There were 218 DFS events reported with trastuzumab compared with 321 DFS events reported with observation. The unadjusted HR for the risk of an event with trastuzumab was 0.64 (0.54–0.76; P < .001), corresponding to an absolute DFS benefit of 6.3%. After a median follow-up of 8 years, the results of the comparison of 1 year versus 2 years of trastuzumab were analyzed. No difference in DFS was found between the groups (HR, 0.99; 95% CI, 0.85–1.14; P = .86).[Level of evidence: 1iiA] The benefit of 1 year of trastuzumab over observation persisted, despite crossover of 52% of the patients on observation (HR, 0.76; 95% CI, 0.65–0.88; P = .0005).[Level of evidence: 1iiA]

In the combined analysis of the NSABP-B-31 (NCT00004067) and Intergroup NCCTG-N9831 trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[Level of evidence: 1iiA] The HERA results were confirmed in a joint analysis of the two studies, with a combined enrollment of 3,676 patients, that demonstrated a highly significant improvement in DFS (HR, 0.48; P < .001; 3-year DFS, 87% vs. 75%), as well as a significant improvement in OS (HR, 0.67; P = .015; 3-year OS, 94.3% vs. 91.7%; 4-year OS, 91.4% vs. 86.6%). Patients treated with trastuzumab experienced a longer DFS with a 52% lower risk of a DFS event (HR, 0.48; 95% CI, 0.39–0.59; P < .001), corresponding to an absolute difference in DFS of 11.8% at 3 years and 18% at 4 years. The risk of distant recurrence was 53% lower (HR, 0.47; 95%CI, 0.37–0.61; P < .001) in patients treated with trastuzumab, and the risk of death was 33% lower (HR, 0.67; 95%CI, 0.48–0.93; P = .015) in these patients.

In the BCIRG-006 (NCT00021255) trial, 3,222 women with early stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T) versus AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab) versus docetaxel, carboplatin, plus trastuzumab (TCH, a nonanthracycline-containing regimen).[Level of Evidence: 1iiA] A significant benefit with respect to DFS and OS was seen in both groups treated with trastuzumab-containing regimens compared with the control group that did not receive trastuzumab. The control group had a 5-year DFS rate of 75% and an OS rate of 87%. For patients receiving AC-T plus trastuzumab, the 5-year DFS rate was 84% (HR for the comparison with AC-T, 0.64; P < .001), and the OS rate was 92% (HR, 0.63; P < .001). For patients receiving TCH, the 5-year DFS rate was 81% (HR, 0.75; P = .04), and the OS rate was 91% (HR, 0.77; P = .04).

The authors stated that there was no significant difference in DFS or OS between the two trastuzumab-containing regimens. However, the study was not powered to detect equivalence between the two trastuzumab-containing regimens. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH) group (P < .001). These trial findings raise the question of whether anthracyclines are needed for the adjuvant treatment of HER2-overexpressing breast cancer. The group receiving AC-trastuzumab showed a small but not statistically significant benefit over TCH. This trial supports the use of TCH as an alternative adjuvant regimen for women with early-stage HER2-overexpressing breast cancer, particularly in those with concerns about cardiac toxic effects.

The AVENTIS-TAX-GMA-302 study was a three-arm large trial containing two anthracycline arms (AC-D: doxorubicin, cyclophosphamide, docetaxel or AC-DH: doxorubicin, cyclophosphamide, docetaxel, and trastuzumab) and a nonanthracycline one (DCbH: docetaxel, carboplatin, trastuzumab). In its second interim efficacy analysis with a median follow-up of 36 months, there were 462 DFS events and 185 deaths. For DFS, the HR was 0.61 for patients in the AC-DH arm (95% CI, 0.48–0.76; P < .001) and 0.67 for patients in the DCbH arm (95% CI, 0.54–0.83; P = .003), compared with the AC-D. This translated to absolute benefits (from years 2 to 4) of 6% and 5%, respectively with the addition of trastuzumab. Nevertheless, longer follow-up is needed in patients in the DCbH arm to warrant the omission of anthracyclines in these patients.

The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC. At a 3-year median follow-up, the risk of recurrence and/or death was significantly reduced in patients receiving trastuzumab (HR, 0.41; P = .01; 95% CI, 0.21–0.83; 3 year DFS, 89% vs. 78%). The difference in OS (HR, 0.41) was not statistically significant (P = .07; 95% CI, 0.16–1.08).[Level of evidence: 1iiA]

Timing of Primary and Adjuvant Therapy

The optimal time to initiate adjuvant therapy is uncertain. A single study that addressed the use of perioperative adjuvant chemotherapy in node-positive patients showed no advantage in DFS when a single cycle of perioperative chemotherapy was given in addition to standard therapy initiated 4 weeks after surgery. A single cycle of immediate postoperative chemotherapy alone was inferior.

A randomized clinical trial (NSABP-B-18) has been performed to evaluate preoperative chemotherapy in the management of patients with stage I or stage II breast cancer. After preoperative therapy with four cycles of doxorubicin and cyclophosphamide, 80% of the assessable patients had a reduction in tumor size of at least 50%, and 36% of the patients had a complete clinical response. More patients treated with preoperative chemotherapy were able to have breast-conservation procedures as compared with those patients in the postoperative chemotherapy group (68% vs. 60%). Twenty-seven percent of the women in the preoperative therapy group for whom a mastectomy had been planned prior to being randomly assigned underwent a lumpectomy. No statistically significant difference existed, however, in DFS, distant DFS, or OS in the patients who received preoperative chemotherapy as compared with those who received postoperative chemotherapy.[Level of evidence: 1iiA]

An EORTC randomized trial (EORTC-10902) likewise demonstrated no improvement in DFS or OS, but showed an increased frequency of conservative surgery with the use of preoperative versus postoperative FEC chemotherapy.[Level of evidence: 1iiA] Preoperative chemotherapy may be beneficial in women who desire breast conservation surgery but who would otherwise not be considered candidates because of the size of their tumor. In a meta-analysis including all trials that compared the use of the same chemotherapy preoperatively and postoperatively, the use of preoperative chemotherapy was associated with a higher rate of local recurrence. Although preoperative chemotherapy affects the results of SLN biopsy, one small study indicated that SLN biopsy technique was feasible in this setting. However, the results of two prospective studies (NCT02031042 and NCT00881361) indicate that SLN biopsy is associated with false-negative rates of 14.2% and 12.6%, respectively, when undertaken after neoadjuvant chemotherapy in patients who convert from a clinically positive to a clinically negative axillary status.[Level of evidence: 3iiD] These rates are higher than those observed when SLN biopsy is done before adjuvant chemotherapy. The role of this procedure in the neoadjuvant setting is uncertain.

HER2-directed therapies

At present, there is no established role for the use of bevacizumab as part of neoadjuvant chemotherapy for breast cancer. Bevacizumab is a monoclonal antibody that works against vascular endothelial growth factor A and has shown some degree of efficacy in the metastatic setting. Two randomized phase III clinical trials of chemotherapy with or without bevacizumab have reported results.

One trial randomly assigned 1,206 patients with primary operable HER2-negative breast cancer to receive chemotherapy with or without bevacizumab. The addition of bevacizumab significantly increased the rate of pCR (28.2% without bevacizumab vs. 34.5% with bevacizumab, P = .02).[Level of evidence: 1iiDiv] However, the addition of bevacizumab increased the rates of hypertension, cardiac toxicity, hand-foot syndrome, and mucositis.

Another study randomly assigned 1,948 patients with operable HER2-negative breast cancer to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel with or without concomitant bevacizumab. The addition of bevacizumab in this study also significantly increased the rate of pCR (14.9% without bevacizumab vs. 18.4% with bevacizumab, P = .003).[Level of evidence: 1iiDiv] Similarly to other clinical trials, the addition of bevacizumab increased toxicity, with higher rates of febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension, but it did not increase surgical complications. A preplanned subgroup analysis subsequently revealed that the addition of bevacizumab to neoadjuvant chemotherapy significantly increased the pCR rate from 27.9% to 39.3% in patients with triple-negative breast cancer (P = .003).[Level of evidence: 1iiDii]

Of note, OS and DFS outcomes were not reported in either clinical trial. Based on these results, bevacizumab should not be used in the treatment of operable breast cancer. Caution should be used in interpreting pCR as a primary clinical outcome. However, further study of bevacizumab for the treatment of operable breast cancer may be warranted.

The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery was studied in a randomized trial. Patients received either chemotherapy first (n = 122), consisting of CMFP plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation, or breast radiation first (n = 122), followed by the same chemotherapy. With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).[Level of evidence: 1iiA] The 5-year crude rates of first recurrence by site in the radiation-first and chemotherapy-first groups, respectively, were 5% and 14% for local recurrence and 32% and 20% for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = .07). Further analyses revealed that differences in recurrence patterns persisted for most subgroups with the exception of those that had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, though the statistical power of these subgroup analyses was low. Potential explanations for the increase in distant recurrence noted in the radiation therapy-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemothera


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