This chapter focuses on the treatment of stage II breast cancer, which encompasses malignancies with primary tumors > 2 cm in their greatest dimension that involve ipsilateral axillary lymph nodes as well as tumors up to 5 cm without nodal involvement.
Stage II breast cancer is further subdivided into stages IIA and IIB. Patients classified as having stage IIA breast cancer include those with T0-1, N1, and T2, N0 disease. Stage IIB breast cancer includes patients with T2, N1, and T3, N0 disease. Therefore, this patient population is more heterogeneous than are the populations with stages 0 and I disease. The pretreatment evaluation and type of treatment offered to patients with stage II breast cancer are based on tumor size, nodal status, status of receptors for estrogen and human epidermal growth factor receptor 2 (HER2, HER2/neu) and Oncotype DX recurrence score.
Surgical and Radiation Treatment
Multiple studies have demonstrated that patients with stage II breast cancer who are treated with either breast-conservation therapy (lumpectomy and radiation therapy) or modified radical mastectomy have similar disease-free and overall survival rates.
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 issued by the National Cancer Institute (NCI) recommended that the breast cancer be completely excised with negative surgical margins and that a level I-II axillary lymph node dissection be performed. Patients should subsequently be treated with adjuvant breast irradiation.
Patients with tumors > 4 to 5 cm may not be optimal candidates for breast conservation due to the risk of significant residual tumor burden and the potential for a poor cosmetic result following lumpectomy (or partial mastectomy). Neoadjuvant chemotherapy, typically used for locally advanced breast cancer, is increasingly used in earlier stage, operable breast cancers to reduce the size of the primary tumor and allow for breast-conserving therapy.
In a study of more than 300 patients treated with neoadjuvant chemotherapy at the MD Anderson Cancer Center, promising results were reported. At a median follow-up of 60 months, the 5-year actuarial rates of ipsilateral breast tumor recurrence (IBTR)-free and locoregional recurrence–free survival were 95% and 91%, respectively. The authors concluded that breast-conservation therapy after neoadjuvant chemotherapy results in acceptably low rates of recurrence-free survival in appropriately selected patients, even those with T3 or T4 disease. Advanced nodal involvement at diagnosis, residual tumor larger than 2 cm, multifocal residual disease, and lymphovascular space invasion predict higher rates of recurrence.
In some patients, preoperative chemotherapy produces a sufficient reduction in tumor size that allows patients to receive breast-conserving therapy. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial showed that preoperative doxorubicin-based chemotherapy decreases tumor size by > 50% in approximately 90% of operable breast cancers, resulting in a greater frequency of lumpectomy.
In a subsequent trial, NSABP B-27, women with invasive breast cancer were randomized to receive 4 cycles of preoperative AC (Adriamycin [doxorubicin] and cyclophosphamide) chemotherapy followed by surgery, or 4 cycles of preoperative AC followed by 4 cycles of docetaxel (Taxotere) then surgery, or 4 cycles of preoperative AC followed by surgery then by 4 cycles of postoperative docetaxel. A higher rate of complete pathologic response was seen at surgery in patients treated with AC followed by docetaxel vs AC alone. There were no significant differences in disease-free and overall survival between the treatment groups. However, those with a complete pathologic response in the breast had significant improvements in disease-free survival (hazard ratio [HR] = 0.45; P < .001) and overall survival (HR = 0.33; P < .001) compared with those who had residual disease after preoperative chemotherapy. Because preoperative chemotherapy does not have a negative impact on survival, the preoperative approach is a reasonable option and has gained favor among many patients.
Preoperative chemotherapy had an ability to convert patients requiring mastectomy to candidates for breast-conserving surgery. However, there was an increase in local recurrence in the “converted” group vs those deemed eligible initially for breast-conserving surgery.
Patients undergoing sentinel lymph node biopsy. A prospective study designed to determine the survival impact of micrometastases in the sentinel nodes of patients with invasive breast cancer included 790 patients who underwent sentinel node biopsy. The investigators found no significant difference in 8-year disease-free or overall survival among patients with micrometastatic tumor deposits in sentinel nodes defined as being pN0(i+) or pN1mic when compared with patients having negative sentinel nodes. The true significance of these micrometastatic deposits is still unclear, but it may help to better define groups of patients who should receive maximum adjuvant medical or surgical therapy or who could avoid additional therapy.
Although helpful in prognosis and treatment planning, completion axillary dissection after a positive sentinel node biopsy may not be required for small tumors and in the absence of lymphovascular invasion. Factors affecting the rate of positive nonsentinel nodes and the necessity of axillary dissection following a positive sentinel lymph node resection were evaluated in NSABP B-32. Women with operable invasive breast cancer and clinically negative nodes were randomized to undergo sentinel node resection with immediate conventional axillary dissection (group 1) or without axillary dissection (group 2). Patients in group 2 who had positive sentinel nodes underwent axillary dissection. Data from 1,166 patients with positive sentinel nodes that were available for multivariate analysis (595 from group 1; 571 from group 2) indicated that a significantly higher percentage of patients in group 2 had positive nonsentinel nodes than did those in group 1 (41.5% vs 35.5%; P = .032). Clinical tumor size was a significant predictor for positive nonsentinel nodes (P = .001). Percentages of patients having positive nonsentinel nodes were significantly increased by the number of positive sentinel nodes, and lymphovascular invasion was a significant predictor for positive nonsentinel nodes. The percentages of patients with positive nonsentinel nodes significantly decreased with increases in the number of hot spots identified and the number of sentinel nodes removed.
The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial is a randomized, multicenter trial designed to determine the effects of completion axillary node dissection on survival of patients with clinical T1 or T2 N0 M0 breast cancer who have one to two positive sentinel nodes. Patients were treated with lumpectomy with whole breast irradiation and adjuvant systemic therapy. Clinical and tumor characteristics were similar between a group of 445 patients randomized to axillary lymph node dissection (ALND) and a group of 446 patients randomized to sentinel lymph node dissection (SLND) alone. At a median follow-up of 6.3 years, locoregional recurrences were uncommon, occurring in 3.1% of ALND and 1.6% of SLND patients (P = .11). Only age (≤ 50 years) and higher Bloom-Richardson scores were associated with locoregional recurrence by multivariate analysis. Number of positive sentinel nodes, size of the sentinel node metastasis, and number of lymph nodes removed were not associated with locoregional recurrence. The omission of ALND in this group of patients did not result in inferior survival. The 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1–94.5) with ALND and 92.5% (95% CI, 90–95.1) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3–86.3) with ALND and 83.9% (95% CI, 80.2–87.9) with SLND alone. A drawback of this study is its early closure and accrual of less than one-half of the targeted enrollment population; nonetheless, its findings have immediate implications for clinical practice. It is important to note that the Z0011 trial did not include patients undergoing mastectomy, lumpectomy without radiotherapy, partial-breast irradiation, or neoadjuvant therapy. In those patients, ALND remains standard practice when SLND identifies a positive SLN.
The timing of sentinel node biopsy in patients undergoing preoperative chemotherapy is controversial. Preoperative chemotherapy can sterilize the axillary nodes and lead to errors in determining nodal involvement. ACOSOG 1071 was designed to determine the application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer. The primary objective of the trial was to determine if the false-negative rate (FNR) for SLN surgery with two or more LNs examined following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer was greater than 10%. A total of 756 women were enrolled, with 649 patients undergoing neoadjuvant chemotherapy followed by both SLN surgery and ALND. Of these 649, a total of 525 patients had two or more SLNs removed. In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85% to 16.05%). Their findings suggest that surgeons cannot reliably detect by SLN procedures all axillary lymph node metastases in patients with cN1 breast cancer following chemotherapy. The authors further concluded that for SLND to become an alternative to ALND in this patient population, changes in approach and patient selection that result in greater sensitivity would be necessary.
For patients with stages I and II breast cancer, radiation therapy following lumpectomy remains an acceptable standard of care. Randomized trials and single-institution experiences have consistently demonstrated a significant reduction in local relapse rates for radiotherapy following breast-conserving surgery. Furthermore, small but significant differences in distant metastasis and disease-free survival have been observed in randomized trials comparing lumpectomy alone with lumpectomy and radiation therapy for patients with invasive breast cancer.
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 standard treatment for the majority of patients with stage II invasive breast cancer.
An update from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) metaanalysis focused on 10,801 women enrolled in 17 randomized trials of radiotherapy vs no radiotherapy after breast-conserving surgery and relates the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk. Overall, radiotherapy reduced the 10-year risk of any first recurrence from 35% to 19.3% (P < .001) and reduced the 15-year risk of breast cancer death from 25.2% to 21.4% (P < .001). In women with pN+ disease (n = 1,050), radiotherapy reduced the 10-year recurrence risk from 63.7% to 42.5% (P < .001) and the 15-year risk of breast cancer death from 51.3% to 42.8% (P = .01).
Radiation dose and protocol. Radiation dose to the intact breast follows the same guidelines used in patients with stages 0 and I disease, described in the previous chapter.
Regional nodal irradiation (RNI). For patients who undergo ALND and are found to have negative lymph nodes, RNI may be employed if the patient has high risk factors such as triple-negative disease, an undissected axilla, or inner/medial quadrant tumors. For patients with positive lymph nodes, radiation therapy to the supraclavicular fossa and/or internal mammary chain may be considered on an individualized basis.
RNI should be administered using careful treatment-planning techniques to minimize the dose delivered to the underlying heart and lungs. Prophylactic nodal irradiation to doses of 45 to 50 Gy results in a high rate of regional nodal control and may improve disease-free survival in subsets of patients.
The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA20 trial evaluated addition of RNI to whole breast irradiation (WBI) following breast-conserving surgery. Whelan et al reported that women with high-risk node-negative or node-positive breast cancer treated with breast-conserving surgery and adjuvant chemotherapy and/or endocrine therapy were randomized to WBI (50 Gy in 25 fractions +/− boost irradiation) or WBI plus RNI (with RNI at 45 Gy, in 25 fractions) to the internal mammary, supraclavicular, and high axillary lymph nodes. A total of 1,832 women were randomly assigned to WBI + RNI (n = 916) or WBI (n = 916). Median follow-up was 62 months. In the study population, 85% of the women had one to three positive nodes, 91% received adjuvant chemotherapy, and 71% got adjuvant endocrine therapy. Compared with WBI alone, WBI + RNI was associated with an improvement in isolated locoregional disease–free survival (HR = .59; P = .02; 5-year risk 94.5% vs 96.8%, respectively), distant disease–free survival (HR = .64; P = .002; 5-year risk 87% vs 92.4%, respectively), disease-free survival (HR = .68; P = .003; 5-year risk 84% vs 89.7%, respectively), and overall survival (HR = .76; P = .07; 5-year risk 90.7% vs 92.3%, respectively). WBI + RNI in comparison to WBI was associated with an increase in grade 2 or greater pneumonitis (1.3% and 0.2% respectively; P = .01) and lymphedema (7.3% and 4.1% respectively; P = .004).
Available data suggest that in patients with positive postmastectomy margins, chest wall fixation, primary tumors > 5 cm, or involvement of four or more lymph nodes at the time of mastectomy, the risk of locoregional failure remains significantly high enough for postmastectomy radiation therapy to be considered.
Several prospective, randomized trials have evaluated the role of postmastectomy radiotherapy in addition to chemotherapy. Most of these trials have been limited to patients with pathologic stage II disease or with T3 or T4 primary lesions. All of these trials have shown an improvement in locoregional control with the addition of adjuvant irradiation, and several recent trials have demonstrated a disease-free and overall survival advantage in selected patients. Clinical practice guidelines developed by the American Society of Clinical Oncology (ASCO) support routine use of postmastectomy radiation therapy for women with stage III or T3 disease or those who have four or more involved axillary lymph nodes.
Most ongoing trials evaluating dose-intensive chemotherapy routinely include postmastectomy radiation therapy to the chest wall and/or regional lymph nodes to minimize locoregional recurrence.
Current recommendations. There is no clearly defined role for postmastectomy irradiation in patients with small (T1 or T2) primary tumors and negative nodes. For patients with one to three positive nodes, postmastectomy radiation therapy may be considered to lower the rate of local relapse and improve disease-free survival, although the benefit is less than that of patients with four or more positive nodes. However, based on the NCIC-CTG MA20 trial, addition of RNI in node-positive patients is beneficial in terms of locoregional control and disease-free survival. For patients with four or more positive lymph nodes, with or without a large primary tumor, postmastectomy radiation therapy should be considered to lower the rate of local relapse and improve disease-free survival. For patients who are younger, or who have T1 or T2 tumors, one to three positive nodes, poorly differentiated subtypes, or lymphovascular invasion, postmastectomy radiation therapy may have a benefit with respect to disease-free and overall survival. However, controversies and uncertainties regarding this issue remain, and individualized decision-making based on the patient’s overall condition and specific risk factors is reasonable.
The EBCTCG conducted a meta-analysis of 8,135 women randomly assigned to treatment groups during 1964 through 1986 in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery vs the same surgery but no radiotherapy. In women who underwent axillary dissection and had no positive nodes (n = 700), radiotherapy did not affect locoregional recurrence or breast cancer mortality. In women who underwent axillary dissection and had one to three positive nodes (n = 1,314), radiotherapy reduced locoregional recurrence (2P < .00001), overall recurrence (2P = .00006), and breast cancer mortality (2P = .01), even in the setting of chemotherapy. Notably, the unirradiated women in these trials with one to three positive nodes had an absolute 10-year risk of overall recurrence of 45.7%, which was reduced to 34.2% by their radiotherapy, so their absolute gain was 11.5%. For 1,772 women with axillary dissection and four or more positive nodes, radiotherapy reduced locoregional recurrence (2P < .00001), overall recurrence (2P = .0003), and breast cancer mortality (relative risk [RR] = 0·87; 95% CI, 0.77–0.99; 2P = .04).
Minimizing pulmonary and cardiac toxicities. Early trials employing postmastectomy radiation therapy showed that the modest improvement in breast cancer mortality was offset by an excess risk of cardiovascular deaths, presumably due to the radiation treatment techniques used, that resulted in delivery of relatively high radiation doses to the heart. Recent trials employing more modern radiation therapy techniques have not demonstrated an excess of cardiac morbidity and, hence, have shown a slight improvement in overall survival due to a decrease in breast cancer deaths. Thus, in any patient being considered for postmastectomy radiation therapy, efforts should be made to treat the areas at risk while minimizing the dose to the underlying heart and lungs.
Radiation dose and protocol. The available literature suggests that doses of 4,500 to 5,000 cGy should be sufficient to control subclinical microscopic disease in the postmastectomy setting. Electron-beam boosts to areas of positive margins and/or gross residual disease reaching doses of about 6,000 cGy and delivered to sites of gross disease, may be considered. At present, in the United States, it is not standard of care to consider hypofractionated regimens in the setting of postmastectomy radiation therapy.
In patients who have undergone axillary lymph node dissection, even in those with multiple positive nodes, treatment of the axillae does not appear to be necessary in the absence of gross residual disease. Treatment of the supraclavicular and/or internal mammary chain should employ techniques and field arrangements that minimize overlap between adjacent fields and decrease the dose to underlying cardiac and pulmonary structures. When treating patients who underwent neoadjuvant chemotherapy who only underwent SLN surgery, care should be taken to comprehensively treat the regional lymph nodes based on the NCIC MA.20 and EORTC trials.
There are two prospective cooperative group trials that will help determine the role of the optimal local therapy after neoadjuvant chemotherapy. The Alliance for Clinical Trials in Oncology cooperative group (formerly known as the American College of Surgeons Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group) trial A011202 examines the role of local therapy in the management of the axilla in patients with residual node-positive disease after neoadjuvant chemotherapy. Patients with cT1-3 N1 disease treated with neoadjuvant chemotherapy will be enrolled, and patients with positive sentinel nodes will be randomly assigned to axillary radiation or completion axillary lymph node dissection. All patients will receive radiation to the breast or chest wall and to the undissected supraclavicular and level III axillary nodes. A companion study by the NRG Oncology group (formerly known as the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group) trial 9353 examines the role of local therapy in the management of the axilla in patients who convert to node-negative after neoadjuvant chemotherapy. Patients with cT1-3 N1 disease treated with neoadjuvant chemotherapy will be enrolled and those with negative sentinel nodes will be randomly assigned to comprehensive nodal irradiation or no nodal irradiation. All patients will receive radiation to the breast or chest wall.