Chapter 27: Early-Stage and Locally Advanced Breast Cancer

Incidence

Breast cancer is the second most common cause of death for women and is the most common cause of death for women age 45 to 55. In 2015, it is estimated that 231,840 American women would be diagnosed with breast cancer and that 40,290 would die from this disease, making breast cancer the second most common cause of cancer-related morality in the United States, with lung cancer being the most common (¹).

In the early 1980s, the rates of breast cancer diagnosis rose sharply, likely related to increased mammographic screening, because it was the incidence of stage 0 and I carcinomas that rose most sharply. Data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute demonstrate that although the incidence of breast cancer has been stable since the late 1980s, there has been an increase in the percentage of breast cancers that are hormone receptor positive, which is thought to be due either changes in receptor assays or an increased use of hormone replacement therapy by women (^2,3). The incidence of primary breast cancer then decreased around 2003, shortly after the publication of the Women’s Health Initiative (WHI) results, which prompted many healthy postmenopausal women to stop using hormone replacement therapy (⁴).

Worldwide Trends

Breast cancer incidence has long varied in different regions of the world. Incidence is highest in Northern Europe and North America and lowest in Asia and Africa. Data suggest that this variability is due not only to environmental factors but also to lifestyle. This is supported by the observation that breast cancer incidence is higher in second-generation Asian immigrants in the United States (⁵).

Mortality

Breast cancer overall mortality rates had been stable for more than 50 years prior to 1989. Starting in the 1990s, there has been a steady decrease in breast cancer deaths every year. Mortality rates declined by 1.4% per year from 1989 to 1995 and by 3.2% per year thereafter. This is thought to be due in part to increased use of mammography, resulting in earlier diagnosis, and the use of effective treatments. Mortality rates continue to be higher for African American women. This is due in part to disparities in health care access that exist both for diagnosis as well as treatment (⁶).

Hereditary

Family History

Although it is known that family history is an important risk factor for breast cancer, only 25% of newly diagnosed patients have a positive family history. The Gail model was the first to incorporate the number of first-degree relatives into a comprehensive model of breast cancer risk assessment (⁷). Claus then assessed the estimated risk of breast cancer based on the number of familial cases and their ages of diagnosis (⁸). It is now well known that the risk for each patient with a positive family history is affected by the age of the family member at diagnosis, the total number of first-degree relatives affected, and the patient’s age. Based on data from a large meta-analysis, the risk of breast cancer for a patient with one affected first-degree relative increased 1.80-fold; if there were two affected first-degree relatives, that risk increased 2.93-fold. This risk was then further modified by the age of the patient, such that a woman’s risk of breast cancer prior to age 40 was increased to 5.7-fold if one relative was diagnosed prior to age 40 (⁹).

Genetic Mutations

The overall prevalence of specific genetic mutations accounting for breast cancer is rare, accounting for only 5% to 10% of all cases. Risk can be further subdivided based on a patient’s history. The most commonly studied mutations are on the BRCA1 and BRCA2 genes, although multiple other mutations exist on genes such as p53, ATM, CHEK2, PTEN, MLH1, MSH2, and PALB2 (¹⁰). In a study that analyzed 10,000 individuals, excluding those with Ashkenazi ancestry, the prevalence of BRCA1 and BRCA2 mutations varied, with a low of 2.9% if the patient and all first- or second-degree relatives had no prior history of breast cancer or ovarian cancer at less than 50 years of age. A maximum prevalence of 81.3% was noted if the patient and any first- or second-degree relative had breast cancer diagnosed at less than 50 years of age and ovarian cancer at any age (¹¹). Because genetic testing often leads to complicated medical decisions both for the patient and other family members, it is important to determine whom it is most appropriate to screen by taking into account population-dependent positive and negative predictive values of the test, using statistical models.

Conditions of the Breast

Ductal Carcinoma In Situ and Lobular Carcinoma In Situ

There has been a rapid increase in the literature concerning the epidemiology, natural history, and treatment of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). (See detailed information in Chapter 30).

With DCIS, the 10-year risk of invasive breast cancer is 5% in the contralateral breast. Lobular carcinoma in situ has been regarded as a risk factor for ipsilateral and contralateral breast cancer. Recent research supports that LCIS is a direct precursor of both invasive lobular and ductal carcinoma. For patients diagnosed with LCIS, the risk of developing breast cancer in either breast is 1% a year (¹²).

Natural Hormonal Factors

Age at Menarche

A later age of menarche is protective. One study has reported that for every 2-year delay in menarche, there was a 10% reduction in breast cancer risk (¹³).

Age at First Pregnancy

There is a favorable risk reduction associated with earlier age of pregnancy. Women who give birth for the first time at age 35 have a 1.6-fold higher risk of breast cancer compared with women who were 26 to 27 at time of first birth. Women who are over age 30 at the time of first birth are at higher risk than nulliparous women (¹⁴).

Age at Menopause

Late menopause is associated with a higher risk of breast cancer. Oophorectomy before age 40 will decrease the lifetime risk of breast cancer by 50% (¹⁵).

Pregnancy

Breast cancer is the second most common cancer associated with pregnancy, with its incidence being 1 in 3,000. The incidence of pregnancy-associated breast cancer is likely related to the delay of childbirth until after age 30. There are controversial data from two reports suggesting that pregnancy might cause a transient rise in breast cancer risk. However, a clearly documented decreased risk of breast cancer occurs 10 to 15 years after childbirth (¹⁶). (See detailed information in Chapter 30.)

Exogenous Hormonal Use

Oral Contraceptives

Most studies have not shown an increased risk of breast cancer with oral contraceptive use (^17,18). However, a meta-analysis showed a significant but small increase in relative risk of breast cancer (¹⁹). A concern about the meta-analysis is that follow-up was limited.

Hormone Replacement Therapy

The WHI showed that the relative risk of breast cancer was increased to 1.26 for women who took combined treatment with estrogen and progesterone for a mean of 5.2 years as compared to placebo (²⁰). Although long-term hormone replacement therapy was associated with a higher risk of breast cancer, short-term use did not seem to significantly increase the risk of breast cancer.

2010 TNM Revisions

The 2010 seventh edition of the Cancer Staging Manual published by the American Joint Committee on Cancer (AJCC) was modified from the prior staging criteria, published in 2002 (Tables 27-1 and 27-2) (²¹).

The changes were based on continuing developments in breast cancer diagnosis and management. Specifically, isolated tumor cells and micrometastases in axillary lymph node staging and M0(i+) for tumor cells in circulation and bone marrow were added. The AJCC also recommended that all specimens have a histologic tumor grade and description of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status.

There is interest in the assessment of prognostic factors in breast cancer. About 30% of patients with node-negative disease will die from a breast cancer–related cause. Thus, there is a great thrust of research to determine markers that could further identify which patients would benefit most from available adjuvant treatment.

Predictive Versus Prognostic Factors

With the growing array of articles in this field, it is important to distinguish predictive prognostic factors. A predictive factor is one that can provide information on the likelihood of response to a given therapeutic intervention. A prognostic factor is one that can provide information on outcome at the time of diagnosis, independent of treatment (²²). Lymph node status is an example of a prognostic factor; ER status is an example of a prognostic and predictive factor.

Pathologic Factors

Prognosis is still determined in large part by histopathology. Multiple studies showed that the most powerful prognostic factor is the extent of disease in the axillary lymph nodes (^23,24). Other important pathologic factors are hormone receptor status, HER2 status, histologic grade, tumor type, and lymphovascular invasion.

Axillary Lymph Nodes

More than 30 years ago, it was established that the number of involved lymph nodes could be used to predict disease-free survival (DFS) and overall survival (OS). The 5-year DFS was 62% with 1 to 3 positive axillary lymph nodes, 58% for 4 to 9 positive lymph nodes, and 29% for ≥10 positive lymph nodes (²⁴).

Nuclear Grade

Nuclear or histologic grade describes the degree of tumor differentiation and is based on a pathologist’s assessment of nuclear size and shape, number of mitoses, and degree of tubule formation. Although a nuclear grade of 1 (most differentiated) to 3 (least differentiated) is reported with every breast cancer pathology report, its use in predicting outcome is still debated (²⁵). This is in part secondary to interobserver variation in the classification of differentiation. The Nottingham combined grading system seems to be most useful because of its semiquantitative approach and is currently recommended by the College of American Pathologists.

Hormone Receptor Status

Estrogen receptor and PR positivity correlate with prolonged DFS and OS. The importance of hormone receptor status has been documented more consistently in node-positive than in node-negative disease. Immunohistochemical assays have now become the favored approach because they can be used with a variety of specimens. A “positive” specimen is defined as at least 1% of positive cells (²⁶).

Proliferative Rate

This can be evaluated by a variety of methods including mitotic figure count, S-phase fraction (the fraction of cells synthesizing DNA) as determined by flow cytometry, thymidine labeling index, and monoclonal antibodies to antigens in proliferating cells. A high S-phase fraction is usually associated with poor differentiation and lack of ER positivity. Antibodies to Ki-67 can be used to determine a proliferative rate that corresponds with the S-phase fraction. A recent meta-analysis showed a positive correlation between high Ki-67 and poor prognosis (²⁷).

HER2/neu Overexpression

The HER2/neu oncogene codes for a 185-kDa transmembrane glycoprotein that has intracellular tyrosine kinase activity and is a member of the family of epidermal growth factor receptors. This group of receptors has an important role in the activation of epidermal signal transduction pathways controlling for epithelial growth and differentiation. Overexpression of the HER2/neu oncogene is present in up to 30% of invasive breast cancers.

The current standard is to perform either fluorescence in situ hybridization (FISH) by single or dual probe or immunohistochemistry (IHC). Breast cancer is defined as HER2-positive overexpressed if IHC is noted to be 3+, which is defined as >10% of membrane staining. By FISH, for single probe, the average copy number is ≥6.0 signals per cell. For dual probe, the HER2/CEP17 ratio should be ≥2.0 or if HER2 copy number is ≥6.0 signals/cell regardless of HER2/CEP17 ratio. Equivocal results include IHC 2+ or dual probe FISH HER2/CEP17 ratio <2.0 and an HER2 copy number between 4.0 and 6.0 signals/cell. These results should be confirmed with the other approved diagnostic tests. If results continue to be equivocal, repeat testing or a new biopsy should be considered (²⁸).

Prior to the introduction of HER2-targeted therapy, overexpression of HER2/neu was associated with shorter DFS and OS (²⁹). A large single-institution study reviewed all women with T1a and T1b disease diagnosed between 1990 and 2002. Multivariate analysis of 965 patients showed that patients with HER2-positive tumors had 5.09 times the rate of recurrence and 7.81 times the rate of distant recurrence at 5 years compared to patients with hormone receptor–positive, HER2-negative tumors (³⁰). The predictive response with HER2 has been demonstrated in prospective randomized controlled trials (discussed later in the “Adjuvant Therapy” section) (^31,32).

Future Thoughts

DNA microarrays classify breast cancer into five major subtypes defined as luminal A, luminal B, basal, HER2 positive, and normal-appearing breast tissue. In a retrospective analysis, these subtypes were associated with differing prognoses (³³). At present, microarrays for these classifications are too expensive to be performed routinely. Cheaper and more cost-effective diagnostics may change the approach.

After definitive local therapy is completed, it is important to plan for adjuvant systemic therapy. The use of chemotherapy, hormonal therapy, and targeted therapy before or after definitive local therapy has had a significant effect on the management and outcomes of breast cancers. All women with node-positive disease and a significant percentage of node-negative women with tumors that are hormone receptor negative or >1 cm in size benefit from chemotherapy. The choice of agents to be used for chemotherapy and hormonal therapy should be guided by the patient’s age, concomitant medical issues, positive or negative axillary lymph node involvement, and the status of the hormone receptors and HER2. Estimation of risk of recurrence and death should be assessed. Adjuvant! Online is a validated model that estimates DFS and OS based on age, comorbidity, tumor size and grade, hormone receptor status, and number of involved lymph nodes (³⁴). Additionally, Oncotype Dx, Mammaprint, and other assays can help stratify risk for hormone receptor–positive, node-negative patients (³⁵).

Chemotherapy

Historical Perspective

Studies in the 1960s and 1970s evaluated whether single-agent chemotherapy after local therapy had any benefit compared with observation alone. The single agents studied included cyclophosphamide, thiotepa, and melphalan. Most reports documented that single agents have modest or no effect on DFS. Subsequently, the focus shifted to polychemotherapy, with most trials evaluating variations of the three-drug regimen of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or similar anthracycline-containing regimens (^36,37).

These polychemotherapy regimens clearly showed a greater benefit in DFS and OS, but it was often unclear to clinicians which regimens were superior or equivalent. The Oxford Overview in 1998 helped clarity this issue by reviewing data from about 18,000 women in 47 trials that compared polychemotherapy or no chemotherapy, about 6,000 women in 11 trials that compared longer versus shorter polychemotherapy, and about 6,000 women in 11 trials of anthracycline-containing regimens versus CMF (³⁸). The final interpretation concluded that adjuvant polychemotherapy for patients under 50 years of age resulted in an absolute improvement in 10-year survival of 7% to 11%, whereas the overall 10-year survival benefit was 2% to 3% for patients age 50 to 69 years.

Anthracyclines

The 1998 Oxford Overview further demonstrated that anthracycline-containing regimens were superior to CMF. There was a statistically significant 12% reduction in risk of recurrence for anthracycline-containing regimens, a 2.7% decrease in mortality, and a 3.2% decrease in relapse. The information gained from this important systematic analysis began a shift toward administration of anthracycline-based regimens for adjuvant therapy of breast cancer.

Official recommendations have been made based on the above data. These were presented at the National Institutes of Health Consensus Development Conference in 2000 and suggested an anthracycline be included as part of breast cancer adjuvant therapy. Several studies have investigated the role of HER2/neu in the positive response to anthracyclines. Both the Cancer and Leukemia Group B (CALGB) 8082 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-11 studies have shown a benefit in DFS in patients who overexpressed HER2/neu and received anthracycline therapy (^39,40).

Evaluation of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) began in 1974 at the University of Texas MD Anderson Cancer Center (MDACC). For 1,107 women with node-positive disease, the results were favorable. The 10-year DFS was 72% for patients with 1 to 3 positive nodes, 55% for patients with 4 to 10 positive nodes, and 36% for those with >10 positive nodes (⁴¹).

Investigations addressing accelerating the delivery of anthracyclines in a dose-dense manner are discussed later.

Taxanes

The role of taxanes for breast cancer treatment was first investigated in metastatic disease. In randomized trials, paclitaxel and docetaxel improved response rates, duration of response, and OS (⁴²). These positive results prompted their investigation in early-stage breast cancer. Several major studies contributed to the current use of taxanes in the adjuvant setting. The CALGB 9344 study evaluated the addition of paclitaxel to doxorubicin and cyclophosphamide (AC) and showed improvements versus placebo in DFS and OS at 69 months of 70% versus 65% and 80% versus 77%, respectively.

The use of docetaxel was evaluated by the Breast Cancer International Research Group (BCIRG) 001 trial, which compared TAC (docetaxel plus AC) versus FAC for the adjuvant treatment of node-positive breast cancer. There was a significant difference in DFS and a trend in OS suggesting docetaxel could reduce the risk of recurrence of breast cancer in the adjuvant setting compared to the standard FAC regimen. However, with the higher rates of myelosuppression and febrile neutropenia seen with TAC, the use of this regimen requires extensive supportive care, including utilization of granulocyte colony-stimulating growth factor (^43,44)

The Eastern Cooperative Oncology Group (ECOG) E1199 trial attempted to define the more effective adjuvant taxane and the optimal schedule of administration (⁴⁵). All patients received a standard dose and schedule of doxorubicin and cyclophosphamide and were randomized to receive paclitaxel (175 mg/m²) every 3 weeks for four cycles, paclitaxel (80 mg/m²) every week for 12 doses, docetaxel (100 mg/m²) every 3 weeks for four cycles, or docetaxel (35 mg/m²) every week for 12 doses. Weekly paclitaxel compared to every 3 weeks was better, with an odds ratio of 1.27 for DFS (P = .006) and 1.32 for OS (P = .01). No significant difference existed between paclitaxel and docetaxel. Paclitaxel every 3 weeks was no longer recommended after this trial (Fig. 27-1).

The US09735 trial was a randomized study that compared four cycles of standard-dose AC with four cycles of docetaxel (75 mg/m²) and cyclophosphamide (TC) (600 mg/m²). Most patients (84.3%) were younger than 65 years old, and 48% were node negative. At a median follow-up of 7 years, there was a significant difference in DFS between TC and AC (81% vs 75%; hazard ratio, 0.74). Additionally, there was a significant difference in OS (87% vs 82%). Febrile neutropenia in older patients was 8% with TC and 4% with AC (⁴⁶). This indicates that TC is a treatment option but should be used with caution in higher risk cancers given the large percentage of young node-negative patients in the study.

Endocrine Therapy

The correlation between the endocrine system and breast cancer was first recognized more than 100 years ago. Beatson first described bilateral oophorectomy in treating inoperable cases of breast cancer (⁴⁷). However, the true understanding of the biological mechanisms that cause estrogen to stimulate the growth of hormone receptor–positive tumors is more recent. Jensen first identified the ER and led subsequent cloning of ER and PR. This knowledge has enabled the development of multiple therapies. Many of these therapies have varying mechanisms of action, but all have the common goal of decreasing estrogen availability for hormone receptor–positive malignancies.

Tamoxifen

Monotherapy

In the late 1970s, tamoxifen was shown to be effective for the treatment of metastatic breast cancer. This form of treatment was well received, because data from trials showed that patients experienced fewer side effects than they did with traditional chemotherapy or with old fashioned endocrine therapy (high-dose estrogens, androgens, adrenalectomy, or hypophysectomy). The proven efficacy of tamoxifen in the metastatic setting enabled its study for adjuvant use.

Tamoxifen was the first targeted drug to be used as an endocrine treatment for early breast cancer. An early placebo-controlled trial of tamoxifen as adjuvant therapy for early breast cancer, NATO, showed that 2 years of tamoxifen treatment reduced treatment failure at 21 months compared with control (14.2% vs 20.5%, respectively) (⁴⁸). Since then, the efficacy of tamoxifen in the adjuvant treatment of primary breast cancer has been demonstrated repeatedly.

Since tamoxifen became available over 35 years ago, a large number of trials investigated its efficacy and tolerability in the treatment of primary breast cancer. Although some individual trials are too small to justify firm conclusions, a meta-analysis has increased confidence in the effectiveness of tamoxifen in improving DFS and OS. Additionally, large cooperative group (NSABP B-14) and international randomized trials (Stockholm and Scottish trials) of tamoxifen versus placebo have demonstrated a clear benefit in DFS and OS (^49,50,51).

An overview of 55 trials studying adjuvant tamoxifen for 1, 2, or 5 years versus no treatment in patients with primary breast cancer showed that tamoxifen treatment produced highly significant benefits in terms of both recurrence of first events and mortality in the hormone receptor–positive population. The reductions in recurrence were 21%, 28%, and 50%, and the reductions in death rate were 14%, 18%, and 28% for 1, 2, and 5 years of tamoxifen treatment, respectively (P < .00001 for each). Tamoxifen treatment for 1, 2, and 5 years also reduced the incidence of contralateral breast cancer by 13%, 26%, and 47%, respectively (⁵²). The benefits occurred almost exclusively in the hormone receptor–positive population. Tamoxifen improves the 10-year survival of women who have ER-positive or ER-unknown tumors.

Further clarification of the optimal treatment duration of tamoxifen was investigated in two large trials: ATTOM (Adjuvant Tamoxifen Treatment Offers More) and ATLAS (Adjuvant Tamoxifen—Longer Against Shorter).

The ATLAS trial enrolled women with early breast cancer who had completed 5 years of tamoxifen and randomly assigned the women to either continue tamoxifen for 10 years or stop at 5 years (⁵³). The risk of recurrence during years 5 to 14 was 21.4% versus 25.1% for women who continued tamoxifen versus those who did not. Breast cancer mortality during years 5 to 14 for women who continued tamoxifen versus the control group was 12.2% and 15.0%, respectively. Pulmonary embolus and endometrial cancer occurred significantly more frequently in the extended tamoxifen group (Fig. 27-2).

The ATTOM trial had a similar design to ATLAS (⁵⁴). Women randomized to continue tamoxifen, versus those who stopped tamoxifen, had significantly less breast cancer recurrence (580 of 3,468 patients vs 672 of 3,485 patients, P = .003) and significantly decreased breast cancer mortality (392 of 3,468 patients vs 443 of 3,485 patients, P = .050). Combining the two trials strengthens the statistical significance of recurrence (P < .0001), breast cancer mortality (P = .002), and OS (P = .005).

With Chemotherapy

The addition of chemotherapy in intermediate- or high-risk groups is recommended (⁵⁵). The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overviews in 1990 showed that chemotherapy in combination with tamoxifen had a beneficial effect in premenopausal women. The 1998 EBCTCG overview (⁵²) showed that the benefits of chemotherapy combined with tamoxifen in patients with ER-positive disease occurred irrespective of age or menopausal status. The benefits of chemotherapy in terms of contralateral breast cancer and improved survival also occurred irrespective of age or menopausal status.

It was not until recently that the appropriate sequence of chemotherapy and hormonal therapy was definitively documented. One difficulty was that evidence had existed in experimental systems that tamoxifen could antagonize the cytotoxic effects of particular chemotherapeutic agents.

One particular study was designed to address the specific timing of tamoxifen therapy (⁵⁶). Patients were divided among three groups: tamoxifen alone, FAC chemotherapy followed by tamoxifen, and concomitant FAC and tamoxifen. Patients were followed up for a median of 8.5 years. The estimated DFS was 67% in the sequential treatment group compared with 62% in the concurrent treatment group.

Aromatase Inhibitors

First Line

Although tamoxifen has proven efficacy for the treatment of hormone receptor–positive breast cancer both alone and in combination with chemotherapy, its usefulness is in part curtailed by its partial estrogen agonist activity. The documented negative secondary effects of tamoxifen include an increased incidence of endometrial cancer, uterine sarcoma, and thromboembolic disease. Thus, there is great interest in exploring other endocrine therapies.

In women whose ovarian function has ceased, the primary remaining estrogen source is the conversion of adrenal androgens to estrogens in peripheral tissues by the cytochrome P450 enzyme aromatase. Aromatase inhibitors (AIs) reduce the availability of estrogen by inhibiting the aromatase enzyme and are indicated for the treatment of breast cancer in postmenopausal women whose ovarian function has ceased (⁵⁷). The first-generation AI aminoglutethimide became available 25 years ago but was limited by excessive toxicity. Newer generation selective AIs, including anastrozole, letrozole, fadrozole, and exemestane, are now available for the treatment of metastatic breast cancer and in the adjuvant setting. Common side effects of all AIs include hot flashes, osteoporosis, arthritis, and joint and muscle pains.

Based on the antitumor activity of the third-generation AIs in the setting of metastatic disease, these drugs were evaluated in the adjuvant setting. The ATAC (Arimidex [anastrozole], Tamoxifen, Alone or in Combination) trial was a double-blind, multicenter study of postmenopausal women with invasive operable breast cancer who had completed primary therapy and were eligible for adjuvant treatment. They were randomized to tamoxifen, anastrozole, or a combination of the two (⁵⁸). Time to recurrence was significantly longer with anastrozole versus tamoxifen in the overall population, with a larger benefit seen in the hormone receptor–positive population. A reduction in the incidence of contralateral breast cancers favored anastrozole, with statistical significance in the hormone receptor–positive population. The DFS estimates at 4 years were 86.9% and 84.5% for anastrozole and tamoxifen, respectively (⁵⁹).

Anastrozole was associated with significantly fewer withdrawals from treatment than tamoxifen (21.9% vs 26.0%, P = .0002) and significantly fewer withdrawals due to adverse events (7.8% vs 11.1%, P < .0001). Anastrozole also resulted in a lower incidence of hot flashes, vaginal discharge, and vaginal bleeding (P < .0001 for each), of ischemic cerebrovascular events and thromboembolic events (P = .0006 for each), including deep venous thrombosis (P = .02), and of endometrial cancer (P = .02). Tamoxifen resulted in a lower incidence of musculoskeletal disorders (including myalgias and arthralgias) and fractures (P < .0001 for both). The tolerability results in the updated analysis showed no major difference from those seen in the first analysis (⁶⁰).

A meta-analysis published in 2010 reviewed the use of AIs versus tamoxifen in postmenopausal women with ER-positive tumors. This review compared AIs as initial monotherapy to tamoxifen monotherapy or as a hormone switch after 2 to 3 years of tamoxifen for a total of 5 years. The conclusion was that AI therapy was associated with a lower rate of recurrence when used as an initial monotherapy or after 2 to 3 years of tamoxifen when compared to tamoxifen monotherapy (⁶¹).

Following Tamoxifen

It is postulated that tamoxifen might stop being effective because breast cancer cells develop resistance to tamoxifen, dependence on tamoxifen, or great sensitivity to circulating estrogen. Consequently, the use AIs after tamoxifen was investigated. The MA-17 trial showed that the addition of letrozole after 5 years of tamoxifen resulted in a significant improvement in DFS (⁶²).

The Breast International Group (BIG) 1-98 trial compared letrozole versus tamoxifen in postmenopausal hormone receptor–positive women and was later amended to include two sequential strategies using letrozole either before or after tamoxifen for a total of 5 years. The results showed that upfront AI reduced the risk of recurrence and improved DFS better than upfront tamoxifen and better than either switching strategy (^63,64).

Another double-blind randomized trial investigated the use of exemestane to complete the 5 years of adjuvant endocrine treatment after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer (⁶⁵). The results showed that exemestane improved the absolute benefit in DFS by 4.7% Thus, exemestane therapy following 2 to 3 years of tamoxifen significantly improved DFS.

The above data for therapy beyond 5 years of tamoxifen is becoming more convincing, and AIs should be considered as extended therapy for high-risk postmenopausal patients. In general, outcomes with antiestrogen therapies are hindered by noncompliance, with 20% to 50% nonadherence rates. This is the same difficulty faced in other disease states, and a cancer diagnosis does not necessarily command optimal compliance with oral therapy. Many barriers influence compliance including medication cost, access to mail-order pharmacies, and a lack of understanding of the benefits of such medicine. A population-based study performed in British Columbia noted that adherence was still difficult even when these oral agents were given free of charge in a country with a national formulary system. Patients who are on oral medication should be followed regularly, and compliance should be reinforced as highly important, as shown in multiple studies, even when drug cost is not a barrier (⁶⁶).

Ovarian Ablation and Suppression

The use of oophorectomy or ovarian irradiation to cause ovarian ablation is an efficacious method for treating early-stage disease in premenopausal patients. The 1996 meta-analysis by the EBCTCG demonstrated that for women below age 50 there was a distinct advantage in OS and DFS when they were treated with ovarian ablation versus no adjuvant therapy. In addition, the outcomes for these patients were similar to those who received the CMF regimen. The ZEBRA trial displayed similar results in hormone receptor–positive patients when comparing a luteinizing hormone–releasing hormone (LH-RH) analog, goserelin, to CMF (⁶⁷).

The TEXT and SOFT trials were designed to determine the value of the addition of adjuvant ovarian suppression to tamoxifen or exemestane in premenopausal hormone receptor–positive breast cancer patients. The patients were randomized to receive tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression for 5 years. In the total population, the addition of ovarian suppression to tamoxifen did not produce a significant benefit. However, in the high-risk cohort who received chemotherapy, ovarian suppression plus tamoxifen improved outcomes when compared to tamoxifen alone. The combined analysis also showed that 5-year DFS with adjuvant endocrine therapy with exemestane was significantly more effective than tamoxifen when ovarian suppression was added. Longer follow-up is needed to evaluate survival data (^68,69).

Ovarian suppression does come at significant costs because the adverse effects are not trivial. In these trials, women receiving ovarian suppression developed significant hot flashes, vaginal dryness, depression, and possible long-term health implications like hypertension, diabetes, and osteoporosis.

HER2 Targeted Therapy

Trastuzumab is a high-affinity humanized monoclonal antibody that recognizes the HER2/neu receptor and is a targeted therapeutic for tumors that overexpress this growth factor receptor. Trastuzumab has been evaluated extensively in the HER2/neu-overexpressing metastatic setting and has been shown to be effective as a single agent both before (⁷⁰) and after chemotherap, (⁷¹) and in combination with multiple agents (⁷²). One notable side effect has been a high rate of cardiotoxicity, particularly when trastuzumab is combined with anthracycline-based chemotherapy. This is due in part to overlapping toxicities and the long half-life of trastuzumab (up to 32 days). The toxicity rarely occurs in patients without a history of cardiac disease and not previously or simultaneously exposed to chemotherapy, especially anthracyclines (⁷³).

Therefore trastuzumab was an accepted and standard therapy for metastatic breast cancer that overexpresses HER2/neu. The safety and efficacy of trastuzumab-based therapy were then established for earlier stage breast cancer with the NSABP B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials, where patients received AC plus paclitaxel with the addition of trastuzumab versus placebo.

The joint analysis of these trials showed an absolute difference in DFS of 12% at 3 years and a 33% reduction in the risk of death (P = .015) (⁷⁴). An updated analysis with a mean time of 8.4 years on study showed a 37% relative improvement in OS (95% confidence interval [CI], 0.54-0.73; P < .001) and an increase in 10-year OS from 75.2% to 84% (⁷⁵).

The BCIRG 006 trial was designed to evaluate the efficacy and safety of docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH) (³²). Patients were randomly assigned to standard doses of doxorubicin and cyclophosphamide followed by docetaxel (100 mg/m²) every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-TH), or docetaxel (75 mg/m²) and carboplatin (area under the curve [AUC] 6 mg/mL/min) plus 52 weeks of trastuzumab (TCH). At a median follow-up of 65 months, the 5-year estimated DFS was 75% for patients receiving AC-T, 84% with AC-T, and 81% with TCH. Estimated rates of OS were 87%, 92%, and 91%, respectively. All trastuzumab regimens were statistically superior for DFS and OS to nontrastuzumab regimens. There were significant difference in both DFS and OS between AC-TH and TCH. Rates of cardiac dysfunction were significantly higher with AC-TH compared with TCH (P = .001).

The PHARE trial attempted to answer the appropriate duration for trastuzumab by comparing 6 versus 12 months of adjuvant therapy. After a median follow-up of 42.5 months, the 2-year DFS rate was 93.8% for the 12-month group versus 91.1% for the 6-month group, with a hazard ratio of 1.28 (95% CI, 1.05-1.56). These results support continuing with the standard of care of 1 year of trastuzumab (⁷⁶).

The HERA trial was also designed to answer the question regarding the optimal duration of trastuzumab. Patients were assigned to observation or 1 or 2 years of trastuzumab. Patients were allowed a variety of standard neoadjuvant or adjuvant chemotherapies and had node-positive or high-risk node-negative disease. A recent update includes mature data from patients receiving trastuzumab for 2 years. Comparing 1 year of trastuzumab versus observation revealed a hazard ratio of 0.76 (95% CI, 0.67-0.86; P < .0001) for DFS and 0.76 (95% CI, 0.65-0.88; P = .0005) for OS despite significant (52%) crossover. No significant differences in DFS or OS were noted between the 1- and 2-year groups (³¹).

Chemotherapy

The concept of giving chemotherapy in the preoperative setting was first evaluated more than 30 years ago for the treatment of locally advanced and inoperable breast cancer. There are multiple possible benefits. One is the ability to downstage a tumor, which would result in making an unresectable tumor operable or enable breast-conserving surgery or segmental mastectomies to be offered to a greater number of patients with operable breast cancer. In addition, there are biological advantages, such as the ability to assess response or resistance to chemotherapy early, delivering the chemotherapy prior to surgical alterations to the vasculature, and using molecular profiling in conjunction with pathologic response to predict outcomes for patients.

In 1978, a study was published that addressed whether there was a benefit for patients with inoperable breast cancer treated with neoadjuvant chemotherapy. A total of 110 patients were enrolled and were treated with doxorubicin and vincristine. Complete response was seen in 16% of patients, and partial response was seen in 55% of patients. All patients also received standard radiation therapy. The 36-month survival rates were 53% for the study group and 41% for the historical controls. The positive results of this study led to other trials (⁷⁷).

The NSABP B-18 trial was the largest to date to investigate neoadjuvant chemotherapy. A total of 1,523 patients with T1 to T3 and N0 to N1 disease were randomized to receive preoperative versus postoperative AC for four cycles (⁷⁸). Results showed a significant increase in lumpectomies in the neoadjuvant group. Final comparison of the two groups showed no difference in DFS or OS at 5 years. This was true for all groups including tumors larger than 5 cm.

Another trial investigated downstaging of axillary nodal metastases after primary chemotherapy (⁷⁹). From Cox regression analysis, it was shown that one of the parameters associated with poor distant disease–free survival was persistent nodal involvement after neoadjuvant therapy. Thus, it was concluded that the response of the axillary nodes to neoadjuvant chemotherapy was a better predictor than the response of the primary tumor.

In general, neoadjuvant therapy with either anthracycline- or taxane-containing regimens has been shown in multiple trials to result in an increase in the number of women able to undergo breast-conserving surgery. Studies have also shown that the use of neoadjuvant therapy, especially with taxanes, can lead to pathologic complete responses (pCRs) as well as clinical responses (⁸⁰). These responses have been well correlated to DFS and OS, making response to preoperative chemotherapy a novel prognostic factor in the treatment of early and locally advanced breast cancer. At this time, the majority of neoadjuvant studies have not yet shown an increase in OS for patients treated with this approach. Preoperative chemotherapy is especially clinically warranted for patients with tumors greater than 3 cm and for axillary node disease.

Endocrine Therapy

Most studies have investigated the potential of using this approach for patients with locally advanced disease rather than early-stage disease. It is a treatment option for women with tumors expressing ER, PR, or both and for patients with low histologic grade tumors.

At this time, neoadjuvant hormonal therapy based on trial results seems to be best suited to women who have locally advanced breast cancer who are otherwise thought to be not suitable for neoadjuvant chemotherapy or whose tumors are noted to be low-grade with expression of ER or PR (^81,82). However, the standard neoadjuvant approach for node-positive or locally advanced breast cancer remains chemotherapy.

HER2 Targeted Therapy

The addition of trastuzumab to standard chemotherapy when given neoadjuvantly has been shown to have improved pathologic responses (⁸³). Additionally, neoadjuvant therapy has helped accelerate approval of promising drugs because clinical and pathologic responses can be quickly obtained.

Dual blockade of the HER2 signaling is currently under investigation. Lapatinib, a tyrosine kinase inhibitor that blocks both HER2 and EGFR, improved progression-free survival when given with capecitabine in the metastatic setting (⁸⁴). In the NeoALTTO trial, trastuzumab and lapatinib (1,000 mg PO daily) were investigated in the neoadjuvant setting. The pCR was significantly higher with both medications (51.3%) versus trastuzumab alone (29.5%; difference 21.1%, 9.1-34.2%, P = .0001) (⁸⁵).

The interest in lapatinib was blunted by the first results from the ALTTO trial presented at the American Society of Clinical Oncology (ASCO) annual conference in Chicago in 2014 (⁸⁶). The four-arm trial compared 1 year of lapatinib alone, trastuzumab alone, or both agents in sequence or in combination. After 4.5 years of follow up, DFS was not significantly different between the patients receiving trastuzumab alone versus the patients receiving the combination. This was surprising given the doubling of the pCR rate seen in NeoALTTO. Additional follow-up is necessary for both trials.

Pertuzumab is a monoclonal antibody that inhibits dimerization with other HER receptors, notably HER3, and binds to an independent domain from trastuzumab. With impressive results in the metastatic setting (⁸⁷), pertuzumab was studied in the neoadjuvant setting.

The NeoSphere trial was designed to evaluate the safety and efficacy of pertuzumab along with trastuzumab in locally advanced, inflammatory, and early HER2-positive breast cancer (⁸⁸). The phase II study randomly assigned patients to four treatment groups: trastuzumab plus docetaxel (75 mg/m², escalating if tolerated to 100 mg/m², every 3 weeks); pertuzumab (loading dose of 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel; pertuzumab plus trastuzumab; or pertuzumab plus docetaxel. After completing this regimen, all patients underwent surgery and then received 5-fluorouracil (600 mg/m²), epirubicin (90 mg/m²) and cyclophosphamide 600 mg/m²) (FEC) every 3 weeks. The results were that 45.8% (95% CI, 36.1%-55.7%) of patients receiving dual HER2-targeted therapy with docetaxel achieved a pCR compared with 29.0% (95% CI, 20.6%-38.5%) of patients receiving trastuzumab and docetaxel alone (Fig. 27-3).

The TRYPHAENA trial was a phase II that explored the tolerability and efficiency of pertuzumab and trastuzumab given with three different chemotherapy regimens (⁸⁹). All patients had HER2-positive node-positive or node-negative disease but at least a total of T2. Two hundred twenty-five patients were randomized to receive one of the following regimens FEC (doses of 500 mg/m², 100 mg/m², 600 mg/m² respectively) with trastuzumab and pertuzumab followed by docetaxel (FEC+H+P × 3 → T+H+P × 3; arm A); FEC followed by docetaxel plus pertuzumab and trastuzumab all at same dose and schedule as (FEC → T+H+P × 3; arm B); or carboplatin (AUC6) and docetaxel plus pertuzumab and trastuzumab (TCHP × 6; arm CC). Upon completion of chemotherapy, all patients underwent surgery and then received adjuvant trastuzumab to complete 1 full year. The majority of patients achieved pCR in the breast (61.6% in arm A, 57.3% in arm B, and 66.2% in arm C), with pCR including lymph nodes in 50.7% (arm A), 45.3% (arm B), and 51.9% of patients (arm C). Eleven patients had declines in left ventricular ejection fraction to less than 50%, and diarrhea was the most common adverse event (Fig. 27-4).

Given the results of these phase II trials, the US Food and Drug Administration granted accelerated approval of pertuzumab in combination with docetaxel for neoadjuvant therapy for node-positive or greater than T2 HER2-positive breast cancer.

Dose Density

One approach to increase response rate to chemotherapy is dose density. This term refers to the administration of chemotherapeutic agents with a shortened interval between treatments, based on the knowledge that a given dose always kills a particular fraction of cancer cells. More frequent administration of cytotoxic therapy may thus be more efficacious than dose escalation to reduce tumor burden. Several recently published trials have explored dose-density regimens.

The CALGB 9741 trial explored the possible superiority of dose-dense over conventional scheduling of adjuvant chemotherapy for node-positive breast cancer (⁹⁰). Patients were randomly assigned to receive doxorubicin, cyclophosphamide, and paclitaxel (175 mg/m²) either in 2-week or 3-week schedules, with growth factor support provided to the dose-dense schedule. At a median follow-up of 36 months, dose-dense treatment improved DFS to 82% (every 2 weeks) versus 75% (every 3 weeks) (P = .01). OS was also improved (92% with every 2 weeks vs 90% with every 3 weeks; P = .013). There was no difference between OS or DFS between the sequential and concurrent schedules.

As noted in the “Taxanes” section, E1199 demonstrated a significant improvement of weekly paclitaxel over paclitaxel every 3 weeks (⁴⁵). It is not clear whether the benefit demonstrated in CALGB 9741 is from the dose-dense nature of the anthracycline or the schedule of the taxane. Additionally, NSABP B-38 found no significant difference in outcomes between TAC for 6 cycles and dose-dense AC with weekly paclitaxel (⁹¹).

Lastly, the Southwest Oncology Group (SWOG) SO0221 trial compared weekly paclitaxel (80 mg/m²) versus dose-dense paclitaxel (175 mg/m²) in node-positive breast cancer patients who had already received AC (⁹²). The results showed equivalent 5-year PFS between the weekly (82%) and biweekly regimens (81%). The weekly schedule was less toxic and did not require growth factor supplementation.

Oncotype DX

Recent efforts have identified multigene assays that can help quantify a patient’s risk of breast cancer recurrence (³⁵). Oncotype DX is a commercially available, validated laboratory test performed on a tumor specimen that analyzes 21 genes associated with receptor expression, proliferation, invasion, and other factors. Calculations based on the expression of these 21 genes result in a recurrence score that relays the likelihood of breast cancer recurrence in the first 10 years after diagnosis (⁹³). These studies found that patients with a low recurrence score derive little benefit from chemotherapy, whereas those with a high recurrence score are likely to benefit from chemotherapy. For women with an intermediate recurrence score, the benefit of chemotherapy was uncertain. To elucidate the benefit of systemic cytotoxic therapy for this middle group, ECOG has designed a trial known at TAILORx, the Trial Assigning Individualized Options for Treatment (⁹⁴). This study randomly assigned node-negative, HER2/neu-negative, hormone receptor–positive women with early breast cancer with a mid-range recurrence score to treatment with either hormonal therapy or chemotherapy followed by hormonal therapy. Disease-free survival, recurrence-free interval, and OS will be compared in these large cohorts.

Data are emerging that perhaps analysis of 21 genes is not better than immunohistochemical analysis of receptor status and Ki-67 percentage. A prognostic score based on staining of ER, PR, HER2/neu, and Ki-67, known collectively as IHC4, correlated with the prognostic information provided by the Oncotype DX score (⁹⁵). This may scale back the elaborate, costly, and time-consuming testing that currently accompanies the evaluation of early-stage breast cancer. The observation regarding IHC4 is based on a single-institution report and requires validation.

The use of a genomic-derived recurrence score helps predict recurrences in patients with node-negative, hormone receptor–positive early breast cancer. However, the details regarding which assay will emerge as most useful, innovative, and cost-effective remain to be seen. The important question is how to manage intermediate-risk patients in terms of adjuvant therapy. Today, intermediate-risk patients should be counseled regarding the uncertainty of their benefit with chemotherapy and encouraged to enroll on clinical trials.

Early-Stage Breast Cancer (Stages I and II)

At MDACC, every effort is made to integrate clinical information with imaging, pathologic staging, and molecular characteristics to optimize treatment efficacy and, whenever possible, perform breast-conserving surgery. A multidisciplinary approach is of upmost importance, especially with regard to planning and combined-modality therapy. Stage I breast cancer includes primary malignancies ≤2 cm in greatest dimension that do not involve the lymph nodes and microinvasive tumors that are ≤0.1 cm in greatest dimension. Stage II breast cancer encompasses primary tumors of 2 to 5 cm that can involve ipsilateral axillary lymph nodes and tumors >5 cm without lymph node involvement. All patients at MDACC (including those with DCIS) undergo receptor testing for hormone receptor status for ER and PR. In addition, patients are tested for HER2/neu status by IHC, and 2+ results are confirmed by FISH.

Stage I

Breast-Conserving Therapy

Breast-conserving surgery (BCS), or segmental resection, has revolutionized patient care for breast cancer over the last two decades. Women are able to preserve their breasts without a negative effect on survival. Breast-conserving therapy involves the surgical removal of tumor followed by radiation therapy to the breast. Multiple studies have shown that patients with stage I breast cancer treated with BCS have DFS and OS rates similar to patients treated with modified radical mastectomies (⁹⁶).

There are only a few true absolute contraindications to BCS, including persistently positive resection margins, multicentric disease, diffuse malignant-appearing microcalcifications, a history of prior radiation to the breast or mantle region (for Hodgkin disease), and pregnancy, although it might be possible to perform BCS in the third trimester. Relative contraindications include a history of connective tissue disease suggesting that radiation would be poorly tolerated, centrally located tumors involving the nipple-areolar complex, and a large tumor in a small breast that might lead to a poor cosmetic result. Although the final decision about whether to offer BCS is left to the discretion of surgical colleagues, most patients who do not meet one of the absolute or relative contraindications are offered this surgical approach.

Risk Factors for Ipsilateral Recurrence With Breast-Conserving Surgery

The risk of ipsilateral tumor recurrence ranges from 0.5% to 2.0% per year. Risk factors include age <35 years, an extensive intraductal component, major lymphocytic stromal reaction, peritumoral invasion, positive margins of resection, and presence of tumor necrosis.

Axillary Lymph Node Dissection

Sentinel lymph node biopsy is the standard of care for patients with clinically negative axilla. In accordance with the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, patients undergoing BCS with T1 or T2 tumors with less than three positive sentinel nodes can forgo complete axillary dissection if they are treated with whole-breast irradiation. Otherwise, if a positive sentinel node is identified, complete axillary node dissection should be performed (⁹⁷).

Radiation Therapy After Breast-Conserving Surgery

Patients with node-negative disease are treated to achieve a total dose of 50 Gy with an approximate dose of 2 Gy/d on a schedule of 5 days per week for a total of 5 weeks. A boost of radiation to the tumor bed is standard. Regional nodal irradiation is no longer used for negative axillary lymph nodes. Radiation is usually begun after chemotherapy is completed, but it can be given concomitantly with hormone-based therapy.

Adjuvant Therapy

HER2-Negative Tumors

Based on data detailed in the earlier section on adjuvant therapy, both pre- and postmenopausal women are offered chemotherapy. We do not routinely give chemotherapy to patients with node-negative breast tumors that are ER positive and/or PR positive and HER2/neu negative. For these patients, we are incorporating the use of the Oncotype DX test for an estimation of the risk of recurrence (see the “Other Systemic Therapy Topics” section). Patients with a low recurrence score are recommended for adjuvant endocrine therapy. Patients with a high recurrence score are counseled for chemotherapy followed by endocrine therapy. Patients with a mid-range recurrence score are offered a choice of either therapy. Our current standard chemotherapy is either dose-dense AC for four cycles followed by weekly paclitaxel for 12 weeks or FAC for 4 weeks preceded by weekly paclitaxel for 12 weeks.

Chemotherapy is usually initiated 2 to 4 weeks after surgery. Studies have shown that delaying chemotherapy for up to 8 to 10 weeks does not have a negative effect on the development of metastasis or survival.

Chemotherapy is administered if the absolute neutrophil count is ≥1,000/μL and platelets are ≥100,000/μL. A complete blood count with differential is checked prior to each chemotherapy cycle and weekly after the first cycle. Growth factor support is always given for dose-dense AC plus paclitaxel and TAC but otherwise is not routinely used. If both chemotherapy and endocrine therapy are used, we give chemotherapy first followed by endocrine therapy. If indicated, radiotherapy follows chemotherapy.

Endocrine Therapy

Estrogen Receptor– and/or Progesterone Receptor–Positive Tumors

Our standard approach, based on previously described information, is to treat receptor-positive stage I disease using a hormonal treatment regimen. Based on the ATAC trial data discussed previously, tamoxifen is given to premenopausal women and AI to postmenopausal women. The ATLAS and ATTOM trials suggest extending tamoxifen to 10 years, which is now recommended. Postmenopausal patients are recommended to receive 5 years of an AI. Endocrine therapies are begun after completion of chemotherapy but can be given concomitantly with radiation therapy (Table 27-4). Given the results of the TEXT and SOFT trials, ovarian suppression therapy is now discussed with premenopausal patients, particularly the younger higher risk patients who received chemotherapy.

HER2-Positive Tumors

Patients with HER2-positive tumors benefit significantly from trastuzumab addition to chemotherapy. For node-negative patients with tumors less than 2.0 cm, the standard of care is AC for four cycles followed by trastuzumab and paclitaxel for 12 weeks or paclitaxel, carboplatin, and trastuzumab for six cycles. Trastuzumab is then given alone to complete 1 full year. If the tumor is hormone receptor–positive, patients are recommended to initiate their antiestrogen therapy once chemotherapy has been completed.

Stage II

Surgery

As with stage I disease, multiple studies of stage II patients treated with either BCS or modified radical mastectomy have documented similar long-term outcomes. Patients with tumors >4 to 5 cm are often not considered to be ideal candidates for BCS because of the potential for residual tumor and poor cosmetic result. These patients are usually treated with neoadjuvant systemic therapy. Patients with strongly ER-positive, PR-positive, HER2-negative, low-grade or low Ki-67 tumors would either have a mastectomy or be offered neoadjuvant endocrine therapy.

Radiation Therapy

After Breast-Conserving Surgery

Radiation of the breast after this form of surgery is similar in terms of area treated and dose given to the treatment of stage I. Regional nodal irradiation to negative axillary lymph nodes is not routinely given. Some groups recommend irradiation of the supraclavicular fossa or internal mammary chain for those with positive lymph nodes.

After Mastectomy

Postmastectomy irradiation should be considered for patients with positive postmastectomy margins, primary tumors >5 cm, or four or more positive lymph nodes. The ASCO clinical care guidelines recommend the routine use of postmastectomy radiation for women with stage III or T3 disease or those with four or more positive lymph nodes (⁹⁸).

According to current recommendations, the dose to be delivered ranges from 45 to 50 Gy. Electron boosts to doses of 60 Gy can be considered if there is gross residual disease or positive margins. Treatment of the axilla in the absence of gross residual disease, even for patients with multiple positive lymph nodes, is not routinely recommended.

Neoadjuvant Therapy

Neoadjuvant therapy is typically given to patients with positive axillary nodal involvement. These institutional guidelines are based on information previously discussed under the sections “Neoadjuvant Therapy” and “Dose Density.” Neoadjuvant therapy for HER2-negative patients uses the same regimens discussed in the adjuvant section. Patients with HER2-positive, node-positive disease or T2 tumors are strongly advised to receive neoadjuvant therapy in order to receive pertuzumab. The regimens offered are those used in the NeoSphere or TRYPHAENA (see Fig. 27-5) clinical trials, while substituting epirubicin for doxorubicin. Following surgery, patients complete a full year of trastuzumab.

Clinical response is documented by serial imaging examinations, usually ultrasound or magnetic resonance imaging. If there is evidence of a level of response that could possibly lead to a tumor pCR, a marker is placed in the breast to identify the primary tumor site. This is done to guide resection, so that if a pCR has occurred, the “scar” tissue from the prior tumor can be resected.

Adjuvant Therapy

Chemotherapy

Patients who do not meet the criteria for neoadjuvant therapy or those who prefer upfront surgery are treated with adjuvant chemotherapy in a fashion similar to those with stage I breast cancer. Data are lacking for pertuzumab in the adjuvant setting. Consequently, patients with HER2-positive breast cancer receive adjuvant chemotherapy regimens with trastuzumab alone.

Endocrine Therapy

Whether patients are treated with neoadjuvant or adjuvant therapy, those with hormone receptor–positive tumors are treated with hormone-based therapy in a similar fashion to those with stage I breast cancer.

Locally Advanced Breast Cancer (Stage III)

About 10% of new patients present with locally advanced breast cancer. These patients usually have easily palpable tumors with large breast masses and/or axillary nodal disease. Inflammatory breast cancer is also included in locally advanced disease and represents 1% to 3% of diagnosed breast cancers. Patients with this very aggressive form of breast cancer can present without a discrete mass and only erythema and edema.

One challenging issue about this group of patients is the heterogeneous nature of their disease, with multiple different subgroups including tumors >5 cm, those with extensive regional lymph node involvement, direct involvement of the skin or chest wall, tumors that have no metastases but are still inoperable, and inflammatory breast cancer. The majority of patients with locally advanced breast cancers will have involved lymph nodes at diagnosis; 50% will have four or more lymph nodes involved. The DFS rates are variable. The most common cause of treatment failure is distant metastases, usually occurring within 2 years of diagnosis. Both locally advanced breast cancer and inflammatory breast cancer can be divided into the same molecular subtypes as operable breast cancer: luminal A and B, HER2, basal-like, etc. Systemic therapy is selected on that basis.

The importance of a multimodality approach cannot be stressed enough. Previously, women with locally advanced disease were classified as being inoperable. Patients who were treated with a single modality of therapy with surgery or radiation had 5-year survival rates of less than 20%. Chemotherapy was first introduced into the treatment algorithm for this subset of breast cancer in the 1970s (⁹⁹). The EBCTCG review noted a modest benefit in survival for patients treated with postoperative chemotherapy (³⁸). The righ risk of developing metastatic disease faced by these patients led to the use of neoadjuvant therapy as part of a multimodality approach.

Neoadjuvant-Based Therapy

Neoadjuvant-based therapy offers many important benefits, including direct in vivo measurement of sensitivity of tumor cells to chemotherapy, which allows for early discontinuation of ineffective therapy. Also, treatment prior to surgical intervention allows the delivery of the chemotherapy through an intact vasculature and thus possibly decreases the probability of developing resistant tumor cells.

Patients with locally advanced disease receive the same chemotherapy as stage II patients. Clinical response is documented by serial physical examinations, mammograms, and ultrasounds of the breast and nodal regions. If there is evidence of response that could possibly lead to a tumor pCR, a radiopaque marker is placed in the breast. Overall, the response to neoadjuvant therapy regimens depends on the patient’s tumors characteristics and the treatment. The tumor effect on the axillary lymph nodes, rather than the response of the primary tumor itself, may be more important in predicting long-term outcome (¹⁰⁰).

Surgery

The historical surgical procedure for locally advanced disease is mastectomy. Clinical trials using neoadjuvant chemotherapy have noted that 50% or more of women with locally advanced breast cancer can be treated with BCS after neoadjuvant therapy (¹⁰¹). One concern is that women who need to be downstaged with preoperative chemotherapy to be eligible for segmental mastectomy have a higher local failure rate (¹⁰²). This can be improved through accurate localization of the tumor using a radiopaque clip, so that the appropriate area of tumor involvement can be resected, even if a complete or near-complete response is achieved with neoadjuvant therapy.

Radiation Therapy

Radiation treatment guidelines recommend that patients with a pathologic response in the primary tumor and axillary lymph nodes, whether they undergo lumpectomy or mastectomy, should receive radiation to the breast and/or chest wall and/or internal mammary lymph nodes to a total dose of 50 to 60 Gy. Patients who achieve a partial response in the primary tumor and have residual nodal disease should have radiation in a comprehensive fashion, including the axillary field.

Adjuvant Therapy

Endocrine Therapy

As in stage I and stage II disease, our standard approach is to treat receptor-positive stage I disease using a hormonal treatment regimen. Based on the ATAC trial data discussed previously, tamoxifen is given to premenopausal women; postmenopausal women receive an AI. The ATLAS and ATTOM trials suggest extending tamoxifen to 10 years. An AI along with ovarian suppression should be considered for this population. Postmenopausal patients are recommended to receive 5 years of an AI. Endocrine therapies are started after completion of chemotherapy but can be given concomitantly with radiation therapy.

Prognosis

Clinical end points have been shown to improve with neoadjuvant therapy involving a combined-modality approach. Patients who are treated with a multimodality treatment approach can achieve long-term survival of 50%. Those who do not respond to neoadjuvant therapy have poorer outcomes. Women who fail to respond to neoadjuvant anthracycline-based therapy remain free of distant disease in only 30% of cases (¹⁰³).

Treatment of breast cancer has evolved from single-agent therapies to more contemporary combinations. Combined-modality approaches with refinement in local therapies (surgery, irradiation) have resulted in progressive improvement in survival in this disease. This is reflected in a single-center series of breast cancer patients treated from diagnosis at our institution from the 1940s to the present (Fig. 27-5).

Over the past six decades, there have been significant advances in the care of early-stage, locally advanced breast cancer. Between 1991 and 2005, the rate of death from breast cancer decreased by 37% in the United States (¹). The use of optimal stage- and hormone receptor–specific therapy is of utmost importance, and can significantly affect the risk of recurrence and death from breast cancer. Outcomes have improved with the addition of neoadjuvant therapy, taxanes, hormonal therapy, and HER2-targeted therapy.