Stage II Breast Cancer

April 16, 2009

This chapter focuses on the treatment of stage II breast cancer, which encompasses primary tumors > 2 cm in greatest dimension that involve ipsilateral axillary lymph nodes as well as tumors up to 5 cm without nodal involvement.

This chapter focuses on the treatment of stage II breast cancer, which encompasses primary tumors > 2 cm in 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 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, and estrogen receptor status.

Treatment

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.

Breast-conservation therapy

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 conservative treatment.

In a study of more than 300 patients treated with neoadjuvant chemotherapy at the M. D. Anderson Cancer Center, promising results were reported. At a median follow-up of 60 months, the 5-year actuarial rates of intrabreast tumor recurrence-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 results in sufficient reduction in tumor response that breast-conserving therapy becomes possible. 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 chemotherapy followed by surgery or 4 cycles of preoperative AC (Adriamycin [doxorubicin] and cyclophosphamide) followed by 4 cycles of docetaxel (Taxotere) followed by surgery, or 4 cycles of preoperative AC chemotherapy followed by surgery followed 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 versus AC alone. There were no significant differences in disease-free and overall survival between the treatment groups. However, those who had a complete pathologic response in the breast had significant improvement in disease-free (hazard ratio [HR], 0.45; P < .0001) and overall survival (HR, 0.33; P < .0001) compared with those with residual disease after preoperative chemotherapy. Since 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 compared with those deemed eligibile initially for breast-conserving surgery.

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 determination of nodal involvement. Formal studies are required to determine whether sentinel node biopsy can be safely performed after the patient has completed neoadjuvant chemotherapy.

Radiation therapy after breast-conserving surgery

For patients with stages I and II breast cancer, radiation therapy following lumpectomy remains an acceptable standard of care. Randomized trials as well as 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 inva-sive breast cancer.

Radiation dose and protocol Radiation dose to the intact breast follows the same guidelines as are used in patients with stages 0 and I disease, described in chapter 9.

Regional nodal irradiation For patients who undergo axillary lymph node dissection and are found to have negative lymph nodes, regional nodal irradiation is no longer employed rou-tinely. For patients with positive lymph nodes, radiation therapy to the supraclavicular fossa and/or internal mammary chain may be consid-ered on an individualized basis.

Regional nodal irradiation 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 4,500 to 5,000 cGy results in a high rate of regional nodal control and may improve disease-free survival in subsets of patients.

Given the wide-spread use of systemic therapy for patients with both node-negative and node-positive disease, the role of axillary dissection has recently come into question. In patients with clinically negative axillae who do not undergo axillary dissection, radiation therapy to the supraclavicular and axillary regions at the time of breast irradiation results in a high rate (> 95%) of regional nodal control with minimal morbidity.

Radiation therapy after mastectomy

Available data suggest that in patients with positive postmastectomy margins, 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 to consider postmastectomy radiation therapy.

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 patients 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 the routine use of postmastectomy radiation therapy for women with stage III or T3 disease or who have four or more involved axillary lymph nodes.

Most ongoing trials evaluating dose-intensive chemotherapy, with or without bone marrow or stem-cell transplantation, 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 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 with T1 or T2 tumors and one to three positive nodes, 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.

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, which 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, to doses of ~6,000 cGy, may be considered.

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.

MEDICAL TREATMENT

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

A discussion of the sequencing of chemotherapy and irradiation and hormonal therapy with irradiation is provided in chapter 9.

Treatment regimens

Systemic adjuvant therapy has been shown to decrease the risk of recurrence and in some cases also the risk of death. Systemic therapy may be divided into chemotherapy and endocrine (hormonal) therapy. Chemotherapy often involves use of combination regimens, given for 4 to 8 cycles. Chemotherapy is most often delivered after primary surgery for breast cancer and before radiation therapy for those who are candidates for irradiation.

Chemotherapy Multiagent therapy with cyclophosphamide, methotrexate, and fluorouracil (5-FU, CMF regimen); cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP); AC; and sequential methotrexate and 5-FU (MF) has been used in patients with node-negative disease (see Table 2 in Chapter 9).

For node-positive disease, systemic chemotherapy has changed over the past few years. Anthracycline-containing regimens are being used with greater frequency and have been shown to be of greater benefit than nonanthracycline-containing regimens (eg, CMF). Epirubicin (Ellence) was approved by the US Food and Drug Administration (FDA) for use in combination with cyclophosphamide and 5-FU (CEF regimen) for the adjuvant treatment of patients with node-positive breast cancer following resection of the primary tumor.

In a pivotal trial conducted by the NCI of Canada, premenopausal women with node-positive breast cancer were randomly allocated to receive either CEF or CMF, administered monthly for 6 months. With a median follow-up of 59 months, the 5-year relapse-free survival rates were 53% and 63% (P = .009), and 5-year survival rates were 70% and 77% for CEF and CMF, respectively (P = .03).

Several trials have also shown the benefit of incorporating taxanes (paclitaxel and docetaxel [Taxotere]) in the adjuvant treatment of node-positive breast cancer, and they are now routinely used in this setting.Taxanes can either be given in combination with an anthracycline or sequentially, either before or after an anthracycline.

The Breast Cancer International Research Group (BCIRG) compared Taxotere (docetaxel), Adriamycin (doxorubicin), and cylophosphamide (TAC regimen) with 5-FU, Adriamycin, and cyclophosphamide (FAC regimen) in 1,480 women with node-positive breast cancer (BCIRG 001/TAX 316). At a median follow-up of 55 months, the estimated 5-year disease-free survival rate

was 75% for patients treated with TAC versus 68% for those treated with FAC. This represents a statistically significant reduction in the risk of relapse of 28% (P = .001).Furthermore, treatment with TAC resulted in a statistically significant reduction in the risk of death (30%; P = .008). Although there was more febrile neutropenia with TAC, it was ameliorated with growth factor support.

In another study by the Cancer and Leukemia Group B (CALGB 9344), 3,121 women with operable, node-positive breast cancer were randomly assigned to receive 3 doses of doxorubicin with a standard dose of cyclophosphamide followed by either no further therapy or 4 cycles of paclitaxel (175 mg/m2). This study did not show any substantial benefit from dose escalation of doxorubicin. However, the addition of 4 cycles of paclitaxel improved disease-free and overall survival. At 5 years, the disease-free survival was 65% and 70%, and overall survival was 77% and 80% after AC versus AC plus paclitaxel, respectively. An unplanned subset analysis showed that the majority of the benefit was seen in those with estrogen receptor-negative tumors. Tamoxifen was given to 94% of patients with hormone receptor-positive tumors. Toxicity was modest with the addition of 4 cycles of paclitaxel.

In a similar study by the NSABP B-28, the addition of paclitaxel (225 mg/m2) did not initially result in improvement of either disease-free or overall survival. However, with longer follow-up (median 67 months), improvement in disease-free survival in favor of AC followed by paclitaxel has emerged.

Dose-dense treatment CALGB 9741 tested two novel concepts: dose density and sequential therapy. A total of 2,005 women with operable, node-positive breast cancer were randomly assigned to receive one of the following regimens: (1) sequential Adriamycin (A) × 4 (doses) followed by Taxol (T) × 4 followed by cyclophosphamide (C) × 4, with doses every 3 weeks; (2) sequential A × 4 followed by T × 4 followed by C × 4, every 2 weeks with filgrastim (Neupogen); (3) concurrent AC × 4 followed by T × 4, every 3 weeks; or (4) concurrent AC × 4 followed byT × 4, every 2 weeks with filgrastim. At a median follow-up of 36 months, there was an improvement in disease-free (risk ratio = 0.74; P =.010) and overall survival (risk ratio = 0.69; P =.013) in favor of dose density. Four-year disease-free survival was 82% for the dose-dense regimens and 75% for the others. There was no difference in disease-free or overall survival between the concurrent (dose-dense) and sequential schedules.

The dosages, schedules, and frequencies of chemotherapy regimens used for node-positive breast cancer are detailed in Table 1. Other regimens also used in node-negative (Chapter 9) and/or metastatic disease (Chapter 11) are listed in their respective chapters.

Jones et al previously reported 5-year results of a randomized trial of 4 cycles of TC compared to 4 cycles of standard AC in women with node-negative (~50%) and node-positive early breast cancer, showing a significant improvement in disease-free survival with a disease-free survival rate of 86% for TC compared with 80% for AC (HR = 0.67; 95% confidence interval [CI], 0.50 to 0.94; P = .015). However, no difference in overall survival was observed, with overall survival rates of 90% for TC versus 87% for AC (HR = 0.76; 95% CI, 0.52 to 1.1; P = .13). With longer follow-up, TC was associated with improved disease-free survival as well as overall survival compared with standard AC. With a median follow-up of now 6.9 years, the difference in overall survival between TC and AC is significant; in the TC group, there were 75 disease-free survival events (15%) and 57 deaths (11%); the AC group had 108 disease-free survival events (21%) and 83 deaths (16%).

The investigators also reported on the effect of treatment by age (using 65 years as the cutoff) on outcome and toxicity. In this trial, 16% (160 patients) were > 65 years of age. Younger women in both the TC and AC groups had less febrile neutropenia (4.4% and 2.3%, respectively) than older women (7.7% and 3.7%, respectively). Toxicity, by treatment, was similar in both age groups to the groups as a whole. The investigators concluded that TC should now be a standard nonanthracycline combination for early breast cancer. In addition, TC was well tolerated in older women without excessive toxicity compared with their younger counterparts, and may be preferable due to its lack of cardiotoxicity.

Recommendations All patients with stage II breast cancer should be considered for systemic adjuvant therapy. Adjuvant chemotherapy in node-positive breast cancer improves disease-free and overall survival by 24% and 15%, respectively. Risk reductions for multiagent chemotherapy are proportionately the same in patients with node-negative and node-positive disease.

Chemotherapy for women 50 years of age and older is similar to that for younger women. However, multiagent chemotherapy affords the greatest benefit in women younger than age 50 with respect to reductions in the risk of recurrence and death from breast cancer. For instance, CMF or AC chemotherapy improves disease-free survival in women aged 50 to 69 by 18%, versus 33% for women younger than age 50. Limited data are available from randomized trials regarding women aged 70 and older. However, in the absence of comorbidity, such as heart, renal, or liver disease, systemic adjuvant therapy can be offered to women > 70 years old.

Endocrine (hormonal) therapy

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview analyses demonstrated a significant advantage with the addition of tamoxifen (20 mg/d oral) for 5 years to the adjuvant therapy regimen of women with estrogen receptor-positive breast cancer regardless of age. Treatment with tamoxifen reduced the risk of death by 14% in women younger than age 50 and by 27% in those 50 years of age and older. Long-term follow-up from the NSABP conclusively demonstrates that there is no benefit to continuing tamoxifen therapy beyond 5 years.However, results from much larger studies have recently reported that a longer duration of tamoxifen may be more beneficial than 5 years of therapy.

Premenopausal women

Approximately 60% of premenopausal women with primary breast cancer have estrogen receptor-positive tumors. For this group of patients, the benefit of adjuvant endocrine therapy, either tamoxifen or ovarian ablation, was established in the EBCTCG overview. Endocrine therapy has comparable efficacy to that of chemotherapy. For premenopausal women, however, the long-term morbidity associated with permanent ovarian suppression may be significant. Ovarian suppression with luteinizing hormone-releasing hormone (LHRH) analogs offers an alternative to permanent ovarian ablation, which is potentially reversible on cessation of therapy.

The Zoladex Early Breast Cancer Research Association (ZEBRA) trial is a randomized trial directly comparing goserelin (Zoladex) monotherapy with CMF in premenopausal women 50 years of age and younger with node-positive, stage II breast cancer. The primary efficacy population included 1,614 patients: 797 randomized to receive goserelin and 817, CMF.Estrogen-receptor status was known for 92.5% of patients; 80% had estrogen receptor-positive tumors.

At a median follow-up of 6 years, the estrogen receptor-positive patients treated with goserelin fared comparably to those who received CMF in terms of disease-free survival (HR = 1.01; P = .94) and overall survival (HR = 0.99; P = .92). Not surprisingly, CMF was superior to goserelin in patients with estrogen receptor-negative tumors. The onset of amenorrhea occurred sooner with goserelin; by 6 months, more than 95% of patients on goserelin were amenorrheic, versus 59% for CMF recipients. Reversibility of amenorrhea was also greater for goserelin; 1 year after cessation of goserelin treatment, 23% remained amenorrheic, versus 77% for CMF recipients.

Several studies have compared adjuvant chemotherapy with combined endocrine therapies in premenopausal women, consisting of tamoxifen for 5 years and an LHRH agonist for 2 to 3 years. Overall, combination endocrine treatment yielded better results than chemotherapy alone. Whether a strategy of combined endocrine therapy is better than tamoxifen alone, either with or without chemotherapy, in premenopausal patients with hormone receptor-positive tumors is the subject of several ongoing clinical trials.

In the Suppression of Ovarian Function Trial (SOFT),following adjuvant chemotherapy, tamoxifen alone is being compared with tamoxifen plus ovarian function suppression/ablation versus ovarian function suppression plus an aromatase inhibitor (exemestane [Aromasin]). The role of ovarian suppression and aromatase inhibitors in this setting is being further investigated by the complementary Tamoxifen and Exemestane Trial (TEXT) comparing ovarian suppression with the

LHRH analog triptorelin (Trelstar) plus tamoxifen versus triptorelin plus exemestane.

Currently, almost all premenopausal women with lymph node-positive, hormone receptor-positive breast cancer receive chemotherapy. Whether combined endocrine therapies alone may be sufficient to achieve excellent outcomes without chemotherapy is a question being investigated in the Premenopausal Endocrine Responsive Chemotherapy (PERCHE) trial. This trial is comparing ovarian function suppression with an LHRH agonist plus chemotherapy followed by tamoxifen or exemestane versus ovarian function suppression and tamoxifen or exemestane without chemotherapy for premenopausal patients with hormone receptor-positive tumors.

Postmenopausal women

For many years, tamoxifen has been the standard adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive tumors. However, demonstrable benefits of aromatase inhibitors, as from several large, randomized clinical trials, have led to increasing use of these agents in the adjuvant treatment of postmenopausal women with hormone receptor-positive tumors.

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was the first large randomized trial demonstrating the superiority of an aromatase inhibitor over tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor-positive breast cancer. After the initial ATAC analyses, the combination arm was closed because of low efficacy. The ATAC trial was recently updated, with a median follow-up of 68 months.

ATAC has shown that anastrozole (Arimidex; n = 3,125) is significantly more effective than tamoxifen (n = 3,116) in preventing recurrences and is better tolerated but associated with a higher risk of fractures on treatment. After treatment completion, fractures and serious adverse events continued to be collected in a blinded fashion.

New data comparing tamoxifen at a median follow-up of 100 months have been presented. Significant improvements were seen for anastrozole compared with tamoxifen for disease-free survival, time to recurrence, time to distant recurrence and contralateral breast cancer. In the hormone receptor-positivepopulation– the results follow: disease-free survival (hazard ratio (HR) 0.85; 95% CI, 0.76–0.94; P = .003),(HR 0.77; 95% CI, 0.67–0.88; P = .0001) TTDR (HR 0.84; 95% CI, 0.72–0.98; P = .027); and CLBC (odds ratio 0.6; 95% CI, 0.42–0.85; P = .004). Absolute differences for anastrozole and tamoxifen increased over time and hazard rates remained lower on anastrozole compared with tamoxifen after treatment completion. Breast cancer deaths were nonsignificantly fewer with anastrozle than tamoxifen (351 vs 380 intent-to-treat; 246 vs 268 hormone receptor-positive), but there was no difference in overall survival (HR = 0.97, hormone receptor-positive). After treatment completion, fracture rates for anastrozole and tamoxifen were similar, and safety benefits were maintained. Myocardial infarction rates on patients were identical to those on or off treatment, and endometrial cancer rates remained lower for anastrozole than tamoxifen off treatment. No new safety concerns were seen. These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for post-menopausal women with hormone-sensitive early breast cancer.

The use of an aromatase inhibitor as up-front adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer was confirmed in the BIG (Breast International Group) 1-98 trial. This study compared letrozole (Femara) with tamoxifen for 5 years as adjuvant endocrine therapy for this patient population. The study was later modified to include a crossover for both agents, but results from the crossover arms have not yet been reported.

At a median follow-up time of 51 months for the monotherapy (non-crossover) arms, 352 disease-free survival events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen were observed. This reflected an 18% reduction in the risk of an event (HR 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports, with patients on tamoxifen experiencing more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding, whereas patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure. The present updated analysis yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.

Other randomized trials have investigated the use of an aromatase inhibitor after tamoxifen. Two sequential strategies after tamoxifen were studied: (1) a switch to an aromatase inhibitor after 2 or 3 years of tamoxifen, to complete a 5-year course of endocrine therapy or (2) a switch to an aromatase inhibitor after 5 years of tamoxifen, to complete 10 years of endocrine therapy, also called extended adjuvant therapy. With either strategy, the use of an aromatase inhibitor after tamoxifen provided significant reduction in events (recurrence, contralateral breast cancer, or death).

In the Intergroup Exemestane Study (IES), 4,742 patients who had received 2 to 3 years of tamoxifen were randomized to receive either additional tamoxifen or a switch to exemestane, to complete a 5-year course of endocrine therapy. After a median follow-up of 55.7 months, 809 events contributing to the analysis of disease-free survival had been reported  (354 exemestane, 455 tamoxifen); unadjusted HR of 0.76 (95% CI, 0.66–0.88; P = .0001) was in favor of exemestane, with an absolute benefit of 3.3% (95% CI, 1.6–4.9) by the end of treatment (ie, 2.5 years after randomization). A total of 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group, with an unadjusted HR of 0.85 (95% CI, 0.71–1.02; P = .08) in the intent-to-treat group. When 122 patients with estrogen receptor-negative disease were excluded, the HR was 0.83 (0.69–1.00; P = .05).Results suggest that early improvements in DFS noted in patients who switch to exemestane after 2 to 3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

Severe toxic events of exemestane were rare, and toxicity profiles were generally similar to those previously reported for aromatase inhibitors. Patients who received exemestane reported fewer venous thromboembolic events than did those on tamoxifen. No other statistically significant differences in reported cardiovascular events (excluding venous thromboembolic events) were noted either on treatment or including the post-treatment period. Myocardial infarctions were rare and occurred in 31 (1.3%) exemestane-treated patients compared with 19 (0.8%) tamoxifen-treated patients (P = .08). Any effect of treatment on the risk of myocardial infarction seemed largely restricted to patients with a history of hypertension. Musculoskeletal pain, carpal tunnel syndrome, joint stiffness, paraesthesia, and arthralgia were reported more frequently in patients who switched to exemestane than in those who remained on tamoxifen. These effects emerged during the on-treatment period. In total, fractures occurred in 277 patients, but hip, spine, and wrist fractures were few. Including on-treatment and post-treatment follow-up, other types of fractures were more common in patients who switched to exemestane than in those on tamoxifen. Fewer clinically serious gynecologic events were reported in patients who switched to exemestane than in those on tamoxifen in the on-treatment period and throughout follow-up. The number of endometrial cancers did not differ significantly between the groups.

Three other randomized trials showed a benefit to switching to anastrozole after 2 to 3 years of tamoxifen treatment versus continued tamoxifen for a total of 5 years. The ITA (Italian Tamoxifen Arimidex) trial, with 448 patients enrolled and a median follow-up of 36 months, showed significant benefits in event-free (HR = 0.35; 95% CI, 0.20–0.63; P = .0002) and recurrence-free survival (HR = 0.35; 95% CI, 0.18–0.68; P = .001) in the women switched to anastrozole. There were 19 total events in the tamoxifen group (n = 225) and 10 in the anastrozole group (n = 223). The 3-year difference in recurrence-free survival was 5.8% (95% CI, 5.2–6.4). Significantly longer locoregional recurrence-free survival (HR = 0.15; 95% CI, 0.03–0.65; P = .003) was noted for the anastrozole group. The difference in distant recurrence-free survival approached statistical significance (HR = 0.49; 95% CI, 0.22–1.05; P = .06).

A combined analysis of the ABCSG (Austrian Breast and Colorectal Cancer Study Group ) Trial 8 and ARNO (Arimidex - Nolvadex) 95 Trial, with 3,224 patients and a median follow-up of 28 months, investigated a similar strategy. It showed that sequential endocrine therapy with tamoxifen for 2 years followed by anastrozole for 3 years was superior to 5 years of tamoxifen in terms of event-free (HR = 0.6; 95% CI, 0.44–0.81; P = .0009) and distant recurrence-free survival (HR = 0.61; 95% CI, 0.42–0.87; P = .0067). No statistically significant difference in overall survival has emerged at this point (P = .16). Updated results from the ARNO 95 trial have recently been reported, indicating that switching to anastrozole resulted in a significant reduction in the risk of disease recurrence (HR, 0.66; 95% CI, 0.44–1.00; P = .049) and improved overall survival (HR, 0.53; 95% CI, 0.28–0.99; P = .045) compared with continuing on tamoxifen. The overall safety profile for anastrozole was consistent with previous reports, and no new safety issues were identified.

In the MA-17 trial, 5,187 postmenopausal women who had taken tamoxifen for 5 years were randomly assigned to receive either letrozole or placebo for an additional 5 years. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial since letrozole therapy after the completion of standard tamoxifen treatment significantly improved disease-free survival. With a median follow-up of approximately 27 months, the 4-year disease-free survival rates for letrozole and placebo were 93% and 87%, respectively (P < .001). No significant difference was noted in overall survival. However, in an updated analysis, an advantage in distant disease-free and overall survival was reported in the subset of women with node-positive disease. Toxicities associated with letrozole were similar to those seen with aromatase inhibitors in other trials.

Bone effects

The third-generation aromatase inhibitors have been shown to reduce bone mineral density (BMD) when compared with tamoxifen in the advanced, adjuvant and neoadjuvant settings in women with early breast cancer. Five-year results from the ATAC trial showed that patients treated with anastrozole had an annual decline in lumbar BMD of 2% during the first 2 years of treatment and ~1% in years 3 to 5.

The bone subprotocol of IBIS-II (International Breast Cancer Intervention Study-II) assessed changes in the BMD in postmenopausal women aged 40 to 70 years with a high risk of breast cancer receiving anastrozole versus placebo for 5 years. To date, of the1,540 women in the prevention study, 613 women have taken part in the bone subprotocol of the study. Of the 250 women whose lumbar spine and femoral neck BMD has been assessed at baseline and 1 year by dual-energy x-ray absorptiometry (DEXA) scans, 162 with normal BMD received only monitoring without bisphosphonate treatment, 59 osteopenic women were further randomized to receive either risedronate (Actonel) or placebo, and 29 osteoporotic women received treatment with risedronate. Data from this trial confirm the BMD losses observed with third-generation aromatase inhibitors on breast cancer patients, but it is also reassuring that BMD loss can be controlled if women receive DEXA scans at baseline and bisphosphonate treatment as needed along with aromatase inhibitors.

ABCSG-12 is a randomized, open-label, phase III, four-arm trial comparing tamoxifen (20 mg/d orally) and goserelin (3.6 mg every 28 days subcutaneously) with or without zoledronic acid (Zometa; 4 mg intravenously every 6 months) versus anastrozole (1 mg/d orally) and goserelin with or without zoledronic acid for 3 years in premenopausal women with endocrine-responsive breast cancer. The median patient age at diagnosis was 44 years. In a BMD subprotocol, patients underwent serial BMD measurements at 0, 6, 12, 24, 36, and 60 months. Of 1,801 patients in the trial, 404 were prospectively included in a bone substudy. A total of 201 patients received adjuvant zoledronic acid together with their endocrine treatment, whereas 203 patients did not. After 3 years of treatment, patients who did not receive zoledronic acid showed a BMD loss of 11.3% as compared with baseline (P < .0001). Bone loss was more pronounced if anastrozole was used in combination with goserelin as compared with tamoxifen (−13.6% vs −9%). At 60 months of follow-up (ie, 2 years after the completion of treatment), patients without zoledronic acid still showed impaired BMD as compared to baseline (−6.8%; P = .0005). In contrast, patients who received zoledronic acid showed unchanged BMD at 36 months (+.3%; P = .85) and increased BMD at 60 months (+3.9%; P = .02).

The Z-FAST study evaluated the efficacy and safety of zoledronic acid in preventing aromatase inhibitors-associated bone loss in postmenopausal women with early breast cancer who are receiving adjuvant letrozole therapy. A total of 602 patients with estrogen receptor-positive and/or progesterone receptor-positive early breast cancer starting letrozole were randomized to up-front zoledronic acid versus delayed zoledronic acid. The delayed group received zoledronic acid when either the post-baseline T-score decreases to < −2 or a clinical fracture occurs. All patients are treated with calcium and vitamin D.

The Z-FAST trial showed that the overall difference in the percentage change in BMD between the up-front and delayed zoledronic acid treatment groups, at both lumbar spine and total hip, progressively increased from baseline through 36 months, demonstrating that zoledronic acid every 6 months for up to 36 months is effective in preventing bone loss associated with adjuvant aromatase inhibitor therapy in postmenopausal women with early breast cancer. At 36 months, the upfront zoledronic acid group (n = 189) showed a mean increase of 3.72% in lumbar spine BMD, whereas the delayed group (n = 188) showed a mean decrease of 2.95%, resulting in an absolute difference of 6.7% (P < .001). The up-front group (n = 189) showed a mean increase of 1.66% in total hip BMD, whereas the delayed group (n = 187) showed a mean decrease of 3.51%, resulting in an absolute difference of 5.2% (P < .001). The study was not designed to detect a significant difference in the fracture rate between treatment arms. It was safe and well tolerated; no serious renal adverse events and no confirmed osteonecrosis of the jaw cases were reported.

Recommendations

Recent guidelines from ASCO and the National Comprehensive Cancer Network (NCCN) highlight the appropriate use of aromatase inhibitors in postmenopausal women with hormone receptor-positive breast cancer. Aromatase inhibitors have a significant role in reduction of recurrence in early-stage breast cancer and should be included as part of the adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive disease. Using an aromatase inhibitor as up-front therapy or switching at some point after 2 to 3 years of tamoxifen is an acceptable strategy. Since the risk of breast cancer recurrence after completion of adjuvant endocrine therapy remains substantial, extended therapy with an aromatase inhibitor is another viable strategy for patients who are completing 5 years of tamoxifen.

Several questions on the optimal use of aromatase inhibitors remain, and we must await completion of ongoing trials and/or development of new trials for answers. For instance, neither the optimal timing nor the duration of aromatase inhibitor therapy has been established, and the role of biomarkers (such as HER2/neu status) in selecting optimal endocrine therapy remains controversial. Furthermore, long-term effects of aromatase therapy, including osteoporosis, have not yet been well characterized.

HER2-positive tumors

HER2/neu-expressing breast cancers have been shown to have a worse outcome than their HER2/neu-negative counterpart. Studies demonstrating significant benefit to the addition of trastuzumab (Herceptin) to chemotherapy in metastatic breast cancer have prompted several groups to test this agent in the adjuvant setting. These studies have completed accrual, and early results are astoundingly positive.

Three major trials of trastuzumab in the adjuvant setting have been published, and results of the fourth trial have been presented. The NSABP B-31 and the North Central Cancer Treatment Group (NCCTG) 9831 were jointly analyzed to include a total of 3,351 HER2-positive patients, with a median follow-up of 2.0 years (2.4 years in trial B-31 and 1.5 years in trial N9831). Both trials included two similar treatment arms: adjuvant chemotherapy with AC followed by paclitaxel with or without weekly trastuzumab for 1 year. Although there were differences between the two studies, including a third treatment arm in N9831 sequencing trastuzumab after paclitaxel that was not included in the joint analysis, the common question addressed was the effect of adding trastuzumab to AC followed by paclitaxel.

There were 261 events in the control group and 133 events in the trastuzumab group. The HR for a first event in the trastuzumab group, as compared with the control group, was 0.48 (95% CI, 0.39–0.59; P < .0001). The percentages of patients alive and disease-free at 3 years were 75.4% in the control group and 87.1% in the trastuzumab group (absolute difference, 11.8 percentage points; 95% CI, 8.1–15.4). At 4 years, the respective percentages were 67.1% and 85.3% (absolute difference, 18.2%; 95% CI, 12.7–23.7). Distant metastases were reported in 193 patients in the control group and 96 in the trastuzumab group. The HR for a first distant recurrence was 0.47 in the trastuzumab group as compared with the control group (95% CI, 0.37–0.61; P < .0001). At 3 years, 90.4% of women in the trastuzumab group were free of distant recurrence, as compared with 81.5% of women in the control group (absolute difference, 8.8%; 95% CI, 5.5–12.1); the respective rates at 4 years were 89.7% and 73.7% (absolute difference, 15.9%; 95% CI, 11.1–20.8). Both disease-free and distant disease-free survival were so highly statistically significant for trastuzumab, such results were unlikely to be due to chance alone.

Furthermore, there appears to be an early survival benefit to the addition of trastuzumab.There were 62 deaths in the trastuzumab group, as compared with 92 deaths in the control group (HR 0.67; 95% CI, 0.48–0.93; P = .015). The absolute survival rate at 3 years was 94.3% in the trastuzumab group and 91.7% in the control group (absolute difference, 2.5%; 95% CI, 0.1–5.0); at 4 years, the respective rates were 86.6% and 91.% (absolute difference, 4.8%; 95% CI, 0.6–9.0 percentage points). The principal adverse event associated with trastuzumab therapy among patients with prior exposure to anthracyclines is cardiac dysfunction.

In trial B-31, for patients initiated on trastuzumab therapy, the cumulative incidence of New York Heart Association (NYHA) class III or IV congestive heart failure or death from cardiac causes at 3 years was 0.8% in the control group (4 patients had congestive heart failure, and 1 died of cardiac causes) and 4.1% in the trastuzumab group (31 patients had congestive heart failure). Of the 31 women in the trastuzumab group who had congestive heart failure, 27 have been followed for at least 6 months after the onset of heart failure, and only 1 reported persistent symptoms of heart failure at the most recent follow-up visit.

In trial N9831, the 3-year cumulative incidence of NYHA class III or IV congestive heart failure or death from cardiac causes was 0% in the control group and 2.9% in the trastuzumab group (20 patients had congestive heart failure, 1 of whom died of cardiomyopathy).

During treatment with paclitaxel alone or with trastuzumab, there was little imbalance between treatment groups in the incidence of any toxicity except for a higher incidence of left ventricular dysfunction in the trastuzumab group. Since the dramatic results are changing the way breast cancer is treated and many clinicians have adopted the use of trastuzumab for similar groups of patients, the same monitoring used in these trials can be adopted in clinical practice to minimize cardiac toxicity. Additional toxicities were rare cases of interstitial pneumonitis, some of which appeared to be related to trastuzumab therapy. In trial B-31, four patients in the trastuzumab group had interstitial pneumonitis, one of whom died. In the N9831 trial, five patients in the trastuzumab group had grade 3+ pneumonitis or pulmonary infiltrates, one of whom died.

The international HERA (Herceptin Adjuvant) trial had a different design and assessed HER2-positive patients who received a variety of chemotherapeutic regimens, randomized to either observation versus 1 or 2 years of every-3-week trastuzumab. Results were reported for only the 1 year of trastuzumab versus the observation arm, which included 5,081 patients with 1-year medial follow-up. Similar to the previously mentioned joint analysis, reduction observed events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were noted for women who received trastuzumab. The unadjusted HR for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95% CI, 0.43–0.67; P < .0001) in favor of trastuzumab. This represents an absolute benefit in terms of disease-free survival at 2 years of 8.4%. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs 37 with observation). Severe cardiotoxicity developed in 0.5% of the women who were treated with trastuzumab.

The BCIRG 006 study evaluated the benefit of adjuvant trastuzumab (H) in 3,222 patients with HER2-positive breast cancer. Unique to this study was a nonanthracycline-containing regimen, which was expected to minimize the cardiotoxicity seen with trastuzumab following anthracycline-based chemotherapy. There were three treatment arms: 1) AC followed by T; 2) AC→TH (docetaxel + trastuzumab); or 3) TCH (docetaxel, carboplatin, trastuzumab).

For the second interim analysis, there were 192, 128, and 142 events in the 3 arms, respectively.HR for (AC→TH vs AC→T) disease-free survival was 0.61 (95% CI, 0.48–0.76; P < .0001), whereas for (TCH vs AC→T) was 0.67 (95% CI, 0.54–0.83; P = .0003). The absolute disease-free survival benefits (from years 2 to 4) were for AC→TH versus AC→T and TCH versus AC→T were 6% and 5%, respectively. There was no statistically significant difference in the disease-free survival between the two trastuzumab-containing arms. HR for (AC→TH vs AC→T) overall survival was 0.59 (95% CI, 0.42–0.85; P = .004), while HR for (TCH vs AC→T) was 0.66 (95% CI, 0.47–0.93; P = .017). There was a statistically significant higher incidence of cardiac events in the AC→TH (20 grade 3/4 events) arm but not in the TCH (4 grade 3/4 events) arm when compared with AC→T (5 grade 3/4 events). There was also a statistically significant higher incidence of asymptomatic declines in left ventricular ejection fraction with AC→TH in comparison to AC→T or TCH. Furthermore, four leukemias were seen in the anthacycline-based arms versus 0 in the TCH arm.Thus, the investigators concluded, that in light of similar efficacy, global safety appears to favor the use of TCH.

There are unresolved questions about the adjuvant use of trastuzumab, including sequential versus concurrent use with chemotherapy, the optimal duration, and whether anthracyclines can be omitted. Furthermore, the long-term safety of trastuzumab in this setting remains to be determined.

High-dose chemotherapy Because of the higher rate of recurrence in patients with stage IIB breast cancer, high-dose chemotherapy can also be considered as part of a clinical trial. See chapter 11 for a discussion of the current status of this approach.

Toxic effects of medical therapy

Chemotherapy The most frequent acute toxicities are nausea/vomiting, alopecia, and hematologic side effects, such as leukopenia and thrombocytopenia. Neutropenia, with its attendant risk of infection, is a potentially life-threatening complication that requires prompt medical attention and broad-spectrum antibiotics until hematologic recovery occurs.

Other toxicities may include amenorrhea, cystitis, stomatitis, myocardial failure, and nail/skin changes. Amenorrhea is drug and dose-related and is often permanent in women older than age 40. Recent evidence demonstrates that chemotherapy-induced ovarian failure in the adjuvant chemotherapy setting is associated with a high risk of rapid bone demineralization in the first 6 to 12 months after treatment. Thus, premenopausal women undergoing adjuvant chemotherapy must be closely evaluated to prevent the development of early osteoporosis. Cardiac failure, although rare, is potentially life-threatening and may be irreversible.

Endocrine therapy Toxicities with tamoxifen or aromatase inhibitors include hot flashes, menstrual irregularities, vaginal discharge, and weight gain. Thrombophlebitis and endometrial hyperplasia are more common with tamoxifen. Arthralgias, osteoporosis, and fractures are more common with aromatase inhibitors, although the incidence of hip fractures is low.

Follow-up of long-term survivors

There is no consensus among oncologists as to the appropriate and optimal follow-up routine for long-term breast cancer survivors. Recommendations for follow-up testing vary. The vast majority of relapses, both locoregional and distant, occur within the first 3 years. Surveillance is most intensive in the initial 5 years; thereafter, the frequency of follow-up visits and testing is reduced (Table 2).

History and physical examination Surveillance methods include a detailed history and physical examination at each office visit. They are performed every 4 to 6 months for 5 years after completion of initial therapy, then annually thereafter. Patients at higher risk of recurrence or complications of treatment may require surveillance at shorter intervals. Patients who have been treated by mastectomy can be seen in the office annually after they have been disease free for 5 years. Patients who were treated with breast-conserving surgery and radiotherapy can be followed at 6-month intervals until they have been disease-free for 6 to 8 years and then annually.

Approximately 71% of breast cancer recurrences are detected by the patients themselves, and they will report a change in their symptoms when questioned carefully. In patients who are asymptomatic, physical examination will detect a recurrence in another 15%. Therefore, a patient’s complaint on history or a new finding on physical examination will lead to the detection of 86% of all recurrences.

Mammography should be performed annually in all patients who have been treated for breast cancer. For patients who have undergone breast-conserving surgery, the first follow-up mammogram should be performed approximately 6 months after completion of radiation therapy. The risk of developing contralateral breast cancer is approximately 0.5% to 1.0% per year. In addition, approximately one-third of ipsilateral breast tumor recurrences in patients who have been treated by conservation surgery and radiotherapy are detected by mammography alone. As the time interval between the initial therapy and follow-up mammography increases, so does the likelihood that local breast recurrence will develop elsewhere in the breast rather than at the site of the initial primary lesion.

Chest x-ray Routine chest radiographs detect between 2.3% and 19.5% of recurrences in asymptomatic patients and may be indicated on an annual basis.

Liver function tests detect recurrences in relatively few asymptomatic patients, and their routine use has been questioned. However, these tests are relatively inexpensive, and it may not be unreasonable to obtain them annually.

Tumor markers There is no evidence that tumor markers, such as carcinoembryonic assay (CEA), CA-15-3, and CA-57-29, provide an advantage in survival or palliation of recurrent disease in asymptomatic patients. Therefore, the use of tumor markers to follow long-term breast cancer survivors is not recommended.

Bone scans Postoperative bone scans are also not recommended in asymptomatic patients. In the NSABP B-09 trial, in which bone scans were regularly performed, occult disease was identified in only 0.4% of patients.

Liver and brain imaging Imaging studies of the liver and brain are not indicated in asymptomatic patients. PET scans are not routinely recommended. Their utility is primarily as an adjunct study, often to establish the extent of metastatic disease.

Pelvic examinations Women with intact uteri who are taking tamoxifen should have yearly pelvic examinations because of their risk of tamoxifen-associated endometrial carcinoma, especially among postmenopausal women. The vast majority of women with tamoxifen-associated uterine carcinoma have early vaginal spotting, and any vaginal spotting should prompt rapid evaluation. However, since neither endometrial biopsy nor ultrasonography has demonstrated utility as a screening test in any population of women, routine use of these tests in asymptomatic women is not recommended.

Bone density Premenopausal women who become permanently amenorrheic from adjuvant chemotherapy and postmenopausal women who are treated with an aromatase inhibitor are at increased risk for bone fracture from osteopenia/osteoporosis. These patients should undergo monitoring of bone health every 1 to 2 years.

SUGGESTED READING

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Chen AM, Meric-Bernstam F, Hunt KK, et al: Breast conservation after neoadjuvant chemotherapy: The M. D. Anderson Cancer Center experience. J Clin Oncol 22:2303–2312, 2004.

Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia B trial 9741. J Clin Oncol 21:1431–1439, 2003.

Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087–2106, 2005.

Coates AS, Keshaviah A, Thurlimann B, et al: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine responsive early breast cancer: Update of study BIG 1-98. J Clin Oncol 25:486–492, 2007.

Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after 2 to 3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092, 2004.

Coombes RC, Kilburn LS, Snowdon CF, et al: Survival and safety of exemestane versus tamoxifen after 2–3 years' tamoxifen treatment (Intergroup Exemestane Study): A randomised controlled trial. Lancet 369:559–570, 2007.

Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after 5 years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793–1802, 2003.

Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983, 2003.

Jakesz R, Kaufmann M, Gnant M, et al: Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after 2 years of adjuvant tamoxifen: Combined results from 3,123 women enrolled in the ABCSG Trial 8 and the ARNO 95 Trial (abstract). Breast Cancer Res Treat 88(suppl 2):S7, 2004.

Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20:4628–4635, 2002.

Kaufmann M, Jonat W, Hilfrich J, et al: Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: The ARNO 95 Study. J Clin Oncol 25:2664–2670, 2007.

Mamounas EP, Bryant J, Lembersky BC, et al: Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28 (abstract). Proc Am Soc Clin Oncol 22:4, 2003.

Martin M, Pienkowski T, Mackey J, et al; Breast Cancer International Research Group 001 Investigators: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302–2313, 2005.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; HerceptinAdjuvant (HERA) Trial Study Team: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672, 2005.

Pierce LJ, Hutchins LF, Green SR, et al: Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23:24–29, 2005.

Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684, 2005.

Thurlimann BJ, Keshaviah A, Mouridsen H, et al: Randomized double-blind phase III study to evaluate letrozole (L) vs tamofixen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer (abstract). J Clin Oncol 23(suppl):6s, 2005.

Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report. J Clin Oncol 23:619–629, 2005.