Epidemiology

Among women who receive regular breast cancer screening with mammograms, less than 5% are diagnosed as having stage III disease. Since the widespread adoption of screening mammography, the percentage of patients diagnosed with LABC has declined. Indeed, according to the Surveillance, Epidemiology, and End Results (SEER) data collected from 1976 through 2008, the incidence of breast cancer with nodal involvement declined among women 40 years of age or older by an absolute rate of approximately 8% (i.e., annual incidence of 78 cases per 100,000 in 2006–2008 compared with 85 cases per 100,000 in 1976–1978). By contrast, according to incidence data collected by the SEER, the National Program of Cancer Registries; and the North American Association of Central Cancer Registries up to 31% of patients with breast cancer diagnosed between 2006 and 2012 had regional metastasis, likely as a function of low rates of regular screening mammograms in the general population. The age distribution of patients who have stage III disease at the time of diagnosis is similar to the age distributions for patients with breast cancer in other stages: approximately 1% of patients are 29 years of age or younger, 9% are 30 to 39 years of age, 22% are 40 to 49 years of age, 20% are 50 to 59 years of age, 19% are 60 to 69 years of age, 18% are 70 to 79 years of age, and 12% are 80 years of age or older. African American and Hispanic women are more likely to be diagnosed with advanced stage breast cancer (stage III and IV) than white women; however, interactions between race and socioeconomic characteristics on stage at diagnosis remain controversial.

Survival

Patients with LABC are at high risk of relapse and death from recurrent, metastatic disease. The long-term outcome of these patients is rarely reported because this patient population usually represents a small subpopulation of trials enrolling patients with early-stage and LABC breast tumors. The National Cancer Database statistics show that patients with stage III disease who underwent modified radical mastectomy and both RT and systemic treatment have a 3-year relative survival rate of 68%, a 5-year relative survival rate of 50%, and a 10-year relative survival rate of 36%. In a retrospective analysis the National Cancer Institute investigated the outcome of 61 patients with noninflammatory stage III breast cancer who received neoadjuvant chemotherapy (i.e., cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin) and hormonal adjuvant treatment. Patients who had a complete response received definitive radiotherapy to the breast and axilla and patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. The 15-year OS was 50% for stage IIIA and 23% for stage IIIB breast cancer. In another series, 831 patients treated with neoadjuvant anthracycline-based chemotherapy regimens, the median follow-up duration was 69.9 months. Patients with LABC included 490 (59%) with inoperable disease at diagnosis. The 5-year recurrence-free and OS rates were 56% and 63%, respectively. More recently 187 patients with HER2 – negative LABC (i.e., clinical stage IIB or III) were treated with dose-dense doxorubicin combined with cyclophosphamide (AC), followed or preceded by nab-paclitaxel in the SWOG S0800. After a median follow-up time of 3 years, the 3-year OS was 87%.

Importantly, LABC represents a heterogeneous group of tumors, with marked variations in biology, clinical patterns of presentation and recurrence, and response to therapy. For instance, the introduction of effective systemic targeted agents, such as trastuzumab, pertuzumab, and lapatinib, led to an improvement in outcomes in a subset of these patients (i.e., patients diagnosed with HER2-postive LABC).

Diagnosis and Staging

LABC can be detected during physical examination or with mammography followed by pathologic diagnosis established by a core needle biopsy. In all cases, estrogen receptor (ER) and progesterone receptor (PR) status, nuclear grade, and HER2 status, and ki67 should be determined on pathologic examination. As neoadjuvant chemotherapy with or without HER2-targeted therapy is considered at diagnosis it is important that radiopaque clips be placed at the time of biopsy to provide localization of disease for future surgical planning. The patient should undergo an imaging evaluation to establish the extent of locoregional disease before initiation of treatment. Diagnostic bilateral mammograms, ultrasonography, and breast magnetic resonance imaging (MRI) should be performed as clinically indicated. Of note, MRI in addition to mammography or mammography and ultrasound has been shown to more accurately delineate the extent of local disease and identify patients for whom breast conserving surgery would be contraindicated. The routine use of MRI for the staging of patients with breast cancer has been limited by the lack of proven benefit for the end points of local recurrences and mortality reduction along with increased cost.

All patients should undergo a thorough physical examination. Current guidelines recommend laboratory evaluation at diagnosis of LABC, including complete blood count, liver function tests, alkaline phosphatase, and chest imaging. Patients in whom any abnormalities are detected on clinical evaluation should undergo imaging with computed tomography (CT) of chest abdomen and pelvis and bone scan. Other tests, such as CT of brain, MRI scans, and/or PET scans should be performed if indicated on the basis of clinical suspicion. Small studies have described the use of F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in the staging of patients with LABC. The detection rates of confirmed distant metastatic disease ranged from 5% to 14%, and the rates of false-positive results in the studies ranged from 0% to 21%. One should keep in mind that equivocal or suspicious sites identified by PET-CT scanning should prompt pathologic confirmation of diagnosis of distant metastatic disease whenever possible as the presence of distant metastatic disease may influence the treatment plan.

PET-CT is superior to CT in the detection of extraaxillary lymph node metastasis; however, the impact on patient outcome is not known. Furthermore, a retrospective study comparing 132 paired bone scans with integrated FDG PET-CTs, in women with stages I–III breast cancer with suspected metastasis, showed a high concordance (81%) for reporting osseous metastases suggesting the a bone scan is not necessary in the setting of a positive PET-CT. In sum, PET-CT could be considered more expensive alternative to CT scans for staging of LABC; however, there is insufficient evidence to support the use of PET-CT for the initial staging evaluation of unselected cases of LABC.

Prognostic Factors

As is true for other types of breast cancer, increasing tumor size, site (i.e., axillary, infraclavicular, supraclavicular, or internal mammary) and number of lymph node metastasis all have independent correlation with disease recurrence and survival are important elements of the staging system. Historical series support the strong correlation between breast cancer survival rates and number of involved nodes, with one study reporting 5-year survival of 73% for patients with metastases in one to three lymph nodes, compared with 46% for patients with metastases in four or more nodes. This correlation is independent of tumor size. The vast majority of these patients did not receive chemotherapy. Increasing size of the primary tumor also has prognostic significance for patients with breast cancer, even in women with tumors larger than 5 cm in diameter.

Tumor expression of ER and/or PR is generally considered a weak favorable prognostic factor and is highly predictive for response to hormonal treatment. Similar to early-stage disease, HER2-positive tumors have a worse outcome in both lymph node–negative and –positive disease. Most importantly HER2 positivity is also a strong predictor of clinical benefit to trastuzumab in combination with chemotherapy. Despite advances in the realm of biomarker-based studies for the adjuvant treatment of node-negative breast cancer, the American Society of Clinical Oncology (ASCO) guidelines do not recommend for the routine evaluation of novel tumor markers such as urokinase plasminogen activator (UPA) and plasminogen activator inhibitor (PAI)-1, p53, cathepsin, cyclin E, PAM50 recurrence score, 70-gene assay, and the Onco type DX assay for patients with lymph node–positive breast cancer due to lack of sufficient evidence in supporting changes in treatment for patients with LABC.

Indeed, in light of poorer prognosis and the presumed benefit of chemotherapy treatment for all patients with LABC; this patient population remains minimally represented in prospective randomized trials and retrospective studies performed to evaluate the clinical utility of genomic predictions assays (e.g., 70-gene assay) in assessing the benefit from adjuvant chemotherapy treatment.

Evolution of Local Therapy

The management of LABC has been challenging and has evolved over time. Initially most patients with LABC were treated with surgery alone and included resection of the breast, lymph nodes, and underlying muscle—the radical mastectomy. Although surgical intervention was possible in most patients, the majority of patients was not cured by surgery alone and ultimately developed metastatic disease, which eventually led to death. For patients with inoperable disease, the role of RT to control the disease was investigated but this therapeutic modality led to many complications due to the high doses of RT needed to control the disease and did not lead to long-term survival. It became clear that a multimodality approach was needed to treat patients with LABC. The emergence of adjuvant systemic therapies gave the physician another tool to treat these complex patients. Randomized trials suggested that adjuvant systemic therapy reduced the incidence of recurrence and death in patients with stage III breast cancer. The effectiveness of systemic therapy varies greatly and is dependent on predictors of therapeutic benefit. A patient with a triple-negative or a HER2-positive tumor will likely respond better to systemic chemotherapy than an ER/PR-positive breast cancer. The ER-positive cancers often do respond to neoadjuvant therapy, but the rate of pathologic complete response (pCR) is not as high as the ER-negative/HER2-positive cancers.

Neoadjuvant systemic therapy given before surgical intervention has increased over the past few decades and has become the standard approach to patients with LABC. It can potentially allow for breast conservation in a patient who was deemed not to be a conservation candidate, and at times it can also make an inoperable candidate operable. The response rate in the primary tumor and regional nodes can vary with the best response seen in ER-negative and HER2-positive cancers.

There have been no differences in DFS or OS in multiple neoadjuvant versus adjuvant therapy trials reassuring both patients and physicians that leaving the tumor intact during neoadjuvant therapy does not impart a worse outcome.

Combined Modality Treatment

A combined modality approach that incorporates radiotherapy, surgery, or both; systemic therapy that includes chemotherapy and targeted agents such as trastuzumab, pertuzumab, and lapatinib; and hormonal therapy when indicated is currently widely used for the management of patients with LABC. This multimodality approach requires careful planning and coordination by a multidisciplinary team. The additional benefit of chemotherapy to surgery and RT was demonstrated in a randomized study of 120 patients with operable stage III breast cancer who were randomized after modified radical mastectomy to receive RT alone; vincristine, doxorubicin (Adriamycin), and cyclophosphamide (VAC) chemotherapy alone; or radiotherapy and VAC chemotherapy. The DFS was better with combined modality of RT and chemotherapy than with surgery alone ( p < .001), and the 3-year OS rates were 57% for patients who received RT alone, 72% for those who received chemotherapy alone, and 90% for those who received both chemotherapy and RT therapy ( p < .01). These early findings supporting a role for adjuvant chemotherapy were confirmed by data from the Early Breast Cancer 2005 Trialists’ Collaborative Group in their meta-analysis of worldwide experience with adjuvant chemotherapy versus no adjuvant chemotherapy in randomized clinical trials of approximately 150,000 women with early-stage cancer. These data demonstrated that adjuvant polychemotherapy produced highly significant reductions in mortality at 15 years of follow-up in women with node-positive breast cancer.

Neoadjuvant chemotherapy is now preferred for patients with LABC because it can downstage tumors and thus increase the rate of breast conserving surgery. In cases of more advanced disease, neoadjuvant chemotherapy can render inoperable tumors resectable. Equivalent OS has been shown for patients who receive neoadjuvant versus adjuvant therapy ( Table 63.1 ). The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 study enrolled 1523 women with T1–T3, N0–N1, and M0 operable breast cancer who were randomized to receive either four cycles of AC given in the neoadjuvant setting or four cycles of the same regimen given as adjuvant therapy. At 16 years of follow-up, no significant differences between the two groups for DFS and OS end points continue to be observed (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.81–1.06; p = .27 and HR 0.99; 95% CI 0.85–1.16; p = .90, respectively). Similar findings were confirmed by the European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Cooperative Group randomized trial of neoadjuvant versus adjuvant chemotherapy in patients with operable breast cancer using a fluorouracil, epirubicin, and cyclophosphamide (FEC) backbone.

The optimal regimen, duration, and sequencing of neoadjuvant chemotherapy have not yet been determined. However, the National Comprehensive Cancer Network (NCCN) guidelines indicate a preference for neoadjuvant regimens that contain both an anthracycline and taxane for patients with LABC given the superior outcome of these regimens in the adjuvant setting for patients with lymph node–positive disease. Among patients with HER2-positive tumors, neoadjuvant trastuzumab-, pertuzumab-, lapatinib, taxane-, and anthracycline-based regimens yield significantly higher clinical complete response (cCR) and pCR rates compared with chemotherapy alone.

Adjuvant hormonal therapy with tamoxifen for premenopausal women or aromatase inhibitors for postmenopausal women improves DFS and is incorporated into the systemic management of patients with LABC as indicated based on the ER and PR status of the tumor. In addition, based on two recent randomized trials, consideration should be given to ovarian suppression combined with antiestrogen therapy for the treatment of premenopausal women with LABC. In the Suppression of Ovarian Function Trial (SOFT) 3066 women with hormone receptor–positive breast cancer were randomized to adjuvant treatment with 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. After a median follow-up time of 67 months, the 5-year DFS rate of 86.6% in the tamoxifen–ovarian suppression arm and 84.7% in the tamoxifen group (HR 0.83; 95% CI 0.66–1.04; p = .10). For patients who received prior chemotherapy the 5-year rate of freedom from breast cancer was 85.7% in the exemestane–ovarian suppression group (HR for recurrence vs. tamoxifen, 0.65; 95% CI 0.49–0.87). Also in the combined analysis of 4609 premenopausal women treated in the SOFT and the Triptorelin With Either Exemestane or Tamoxifen (TEXT) trials (the latter also randomized premenopausal women to ovarian suppression combined with tamoxifen or exemestane for 5 years), the 5-year DFS was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (HR 0.72; 95% CI 0.60–0.85; p < .001). Taken together, the results of these trials suggest that ovarian suppression combined with antiestrogen therapy for 5 years should be considered for women with high-risk breast cancer, such as hormonal receptor–positive LABC.

Furthermore, in the ATLAS trial, 12,894 women with early-stage breast cancer were randomized to continuation of tamoxifen for 5 years or to stop after completion of 5 years of tamoxifen. Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence ( p = .002), and reduced breast cancer mortality ( p = .01). Of note, only approximately 10% had tumors measuring more than 5 cm, and approximately 25% had N1–N3 disease. Similar results were observed in the UK Adjuvant Tamoxifen: To Offer More? trial (aTTom) trial. Increased length of adjuvant treatment with tamoxifen from 5 to 10 years should be considered for premenopausal women with high risk of disease recurrence.

The NCCN guidelines recommend postmastectomy RT for all patients with pathologic confirmation of four or more positive axillary lymph nodes, T ₃ tumors, or clinical stage III disease. For patients treated with neoadjuvant systemic therapy, indications for RT and treatment fields should be based on the maximum stage from the pretherapy clinical stage, pathologic stage, and tumor characteristics.

In a recent update the ASCO, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline recommend that patients with axillary nodal involvement after neoadjuvant systemic therapy should receive postmastectomy RT. Adjuvant RT should generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast. In a retrospective review of 150 patients (48% with stage IIIA or IIIB disease) treated with neoadjuvant chemotherapy followed by mastectomy at the MD Anderson Cancer Center, the 5- and 10-year rates of local-regional recurrence were both 27%. In patients with clinical stage III disease at diagnosis, the 5-year locoregional recurrence rate was 20%. In patients with clinical stage III disease who attained a pCR, the 5-year locoregional recurrence rate remained elevated at 33%. Increased pathologic tumor size and number of residual involved lymph nodes were associated with higher 5-year rates of locoregional recurrence. Data from the NSABP B-18 and B-27 studies that randomized stage II and III patients to receive neoadjuvant or adjuvant chemotherapy prohibited the use of postmastectomy RT, and patients who underwent lumpectomy received breast RT only. In both studies, posttreatment pathologic lymph node involvement was a strong predictor of DFS and OS ( p < .0001).

There are no randomized studies evaluating the benefit of postmastectomy RT in patients treated with neoadjuvant chemotherapy. Huang and coworkers compared the outcome of 542 patients (73% with stage III disease) enrolled on several neoadjuvant chemotherapy trials who received mastectomy and RT with a cohort of 138 patients (46% with stage III disease) who received similar treatment but who did not receive RT. Patients who received postmastectomy RT had a lower 10-year rate of locoregional recurrence (8%) compared with those who did not receive RT (22%). RT also significantly improved the overall and cause-specific survival in patients with stage IIIB and IIIC disease and patients with four or more residual involved lymph nodes. It is recommended that patients with baseline tumor characteristics that predict an increased risk of local-regional recurrence receive postmastectomy RT after neoadjuvant therapy regardless of clinical response. This clinical practice requires the early involvement of the radiation oncologist in the multidisciplinary treatment planning of patients with locally advanced breast cancer.

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy for the treatment of breast cancer was introduced in the 1970s for patients with locally advanced disease. The terms neoadjuvant, primary, preoperative, and induction are all used to describe systemic chemotherapy given as initial therapy. Administering chemotherapy before other treatments has many theoretical advantages. Neoadjuvant chemotherapy can result in downstaging of tumors, thus increasing the rate of breast conserving surgery. In cases of more advanced disease, neoadjuvant chemotherapy can render inoperable tumors resectable. Other advantages of neoadjuvant therapy include the ability to obtain information on tumor response, which can be used to study the biologic effects of chemotherapy and determine long-term DFS and OS.

The NCCN guidelines indicate a preference for neoadjuvant regimens that contain both anthracycline and taxane for patients with LABC. Dieras and colleagues compared neoadjuvant AC and doxorubicin with paclitaxel (AP), and higher cCR and pCR rates were associated with AP (cCR 15%, pCR 16%) than AC chemotherapy (cCR 7%, pCR 10%). Breast conserving surgery was more frequent in the AP arm (58%) than the AC arm (45%; p value not provided). Similar findings of a higher cCR and pCR were seen in the Anglo-Celtic Cooperative Oncology Group study that compared the combination of doxorubicin with docetaxel (AD) and AC. However, breast conserving surgery rates were equivalent (20%). Steger and coworkers investigated whether six cycles of epirubicin and docetaxel (EC) resulted in a higher rate of pCR than three cycles of the same regimen in 262 breast cancer patients with stage II and III disease. Six cycles of EC compared with three cycles of EC resulted in a higher pCR (18.6% vs. 7.7%, respectively, p = .0045) and a trend toward a higher rate of breast conserving surgery.

Several randomized studies have also investigated the sequential administration of taxanes after an anthracycline-based regimen and have shown higher rates of pCR. In the seminal NSABP B-27 study, which included 2344 patients with stages II and III breast cancer, all patients were assigned to receive four cycles of AC before surgery. Arm 1 received no further treatment, arm 2 received sequential neoadjuvant docetaxel for four cycles, and arm 3 received adjuvant docetaxel for four cycles. After surgery and RT for patients who underwent lumpectomy, all patients received tamoxifen regardless of age or ER or PR status. Eighty-six percent of patients who received neoadjuvant AC alone (arms 1 and 3) experienced a clinical response compared with 91% of patients who received neoadjuvant AC and sequential docetaxel chemotherapy ( p < .001). The pCR rate increased from 13% to 26%. The improvement in pCR with the addition of docetaxel did not translate into an improvement in DFS or OS, although relapse-free survival favored the neoadjuvant docetaxel arm. Similar findings were seen in the German Preoperative Adriamycin Docetaxel study, which randomized 904 patients with stage II and III breast cancer to receive four cycles of doxorubicin and docetaxel (AD) chemotherapy or four cycles of AC chemotherapy followed by four cycles of docetaxel. The arm that contained sequential administration of docetaxel resulted in a higher pCR (14.3%) compared with the combination arm (7%; p < .001). The sequential administration of taxanes also provides benefit for patients who fail to respond to an anthracycline-based neoadjuvant regimen. In a study of 167 patients with LABC, responders to four cycles of neoadjuvant cyclophosphamide, vincristine, doxorubicin, and prednisolone (CVAP) chemotherapy were randomized to receive either four additional cycles of CVAP or four cycles of docetaxel; nonresponders were all treated with four cycles of docetaxel. Patients who received docetaxel showed significantly higher clinical and pathologic response rates and significantly better 3-year survival rates (97% vs. 84%, p = .02).

The question of the potential benefit to the addition of antiangiogenic therapy to chemotherapy has also been addressed in clinical trials. In the GeparQuinto trial a total of 1948 women with HER2-negative, operable breast tumors were randomized to neoadjuvant treatment with epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab (a vascular endothelial growth factor–directed antibody). The pCR rate was 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab ( p = .04). In parallel the NSABP B-40 trial assessed the efficacy of bevacizumab combined with docetaxel followed by treatment with AC in 1206 women with HER2-negative, operable tumors. The addition of bevacizumab to the AC backbone significantly increased the pCR rate from 28.2% without bevacizumab to 34.5% with bevacizumab ( p = .02). No survival advantaged was observed with the addition of bevacizumab to neoadjuvant chemotherapy in either trial.

The SWOG 0800 study was a phase II trial which accrued 215 patients with inflammatory or LABC. In one arm of the study, patients were treated with nab-paclitaxel combined with bevacizumab followed by AC, which was compared with nab-paclitaxel followed or preceded by AC. The addition of bevacizumab significantly increased the pCR rate overall (36% vs. 21%; p = .019) and in triple-negative breast cancer (TNBC; 59% vs. 29%; p = .014) compared with chemotherapy alone, but not in hormone receptor–positive disease (24% vs. 18%; p = .41). A trend for improved event-free survival with bevacizumab was seen among patients with TNBC ( p = .06). However, in light of the low magnitude of effect observed in these and other trials for increased pCR rates and the lack of improvement in DFS and OS with the addition of bevacizumab in the adjuvant setting, bevacizumab is not recommended for the neoadjuvant treatment of breast cancer.

The clinical utility of the addition of non–cross-resistant chemotherapy agents to anthracycline-cyclophosphamide-taxane backbone has been studied by numerous trials. For example, the previously described NSABP B-40 trial also assessed the efficacy of additional neoadjuvant therapy consisting of docetaxel, docetaxel plus capecitabine, or docetaxel plus gemcitabine for four cycles, with all regimens followed by treatment with AC for four cycles. The addition of either capecitabine or gemcitabine to docetaxel therapy did not significantly increase the rate of pCR rates (30% and 32%, respectively, vs. 33%; p = .69).

Notwithstanding the lack of benefit of additional chemotherapy to unselected patients with nonmetastatic breast cancer the Cancer and Leukemia Group B (CALGB) 40603 trial showed increased pCR (i.e., absence of invasive disease in the breast or lymph nodes) in patients the operable TNBC treated with addition carboplatin. The CALGB 40603 trial had a 2 × 2 factorial design trial in which 443 women with stage II to III TNBC received paclitaxel for 12 weeks, followed by AC for four cycles, and were randomly assigned to concurrent carboplatin once every 3 weeks for four cycles and/or bevacizumab once every 2 weeks for nine cycles. The addition of either carboplatin (60% vs. 44%; p = .0018) or bevacizumab (59% vs. 48%; p = .0089) significantly increased pCR in the breast alone, whereas only carboplatin (54% vs. 41%; p = .0029) significantly raised pCR in both breast and axilla. Likewise, in the GeparSixto, patients with stage II–III TNBC received neoadjuvant treatment with bevacizumab combined with weekly paclitaxel and pegylated liposomal doxorubicin ± carboplatin. A total of 84 of 158 patients (53%, 95% CI 54.4–60.9) treated with carboplatin achieved a pCR compared with 58 of 157 (37%, 95% CI 29.4–44.5) without ( p = .005). Grade 3 and 4 hematological and nonhematologic adverse events were more common among patients treated with carboplatin (i.e., neutropenia 65% vs. 27%, anemia 15% vs. one <1%, thrombocytopenia 14% vs. one <1%), and diarrhea 17% vs. 11%). These results along with the lack evidence of survival benefit with the addition of carboplatin to neoadjuvant treatment of breast cancer indicate that further studies are needed to establish the role of platinum agents for the treatment LABC.

Furthermore, caution should be taken when comparing the rates of cCR and pCR between neoadjuvant studies because of the different criteria used to define these outcomes.

In recent meta-analysis of 12 randomized trials that pooled data from 11,955 patients undergoing neoadjuvant breast cancer treatment, absence of invasive disease from the breast and lymph nodes showed greater magnitude and strength of correlation with event-free survival (EFS) and OS than absence of invasive disease from the breast alone. Patients with HER2-postive, hormone receptor–negative breast cancer treated with trastuzumab and TNBC who achieved a pCR (i.e., absence of invasive disease in the breast and lymph nodes) had significantly better outcomes; EFS: HR 0.15; OS: HR 0.08 and EFS: HR 0.24; OS: HR 0.16, respectively. In the overall HR-positive population the magnitude of correlation between pCR and EFS and OS was lower despite statistical significance (EFS: HR 0.49 and OS: HR 0.43). These results indicate that pCR indeed conveys prognostic information particularly in patients with aggressive tumors.

Neoadjuvant Anti-HER2-Based Therapy

Anti-HER2-targeted therapies have been integrated into the neoadjuvant setting in combination with chemotherapy for the treatment of patients with LABC. In the majority of studies, tumors were considered HER2-positive if the immunohistochemical (IHC) assay (DAKO) showed 3+ staining or there was gene amplification by fluorescent in situ hybridization (FISH). Because of concerns regarding the elevated rate of cardiac toxicity associated with the combination of anthracyclines and trastuzumab, neoadjuvant studies have focused predominantly on combining trastuzumab with taxane-based regimens. Historically numerous small studies demonstrated promising increased efficacy of trastuzumab-based neoadjuvant chemotherapy regimens for patients with HER2 – positive tumors.

Indeed, in more recent larger randomized trials, efficacy of neoadjuvant treatment with trastuzumab-chemotherapy combinations was confirmed. The NeOAdjuvant Herceptin (NOAH) trial enrolled 235 women with HER2 – positive LABC or IBC and randomized to neoadjuvant treatment with chemotherapy with or without trastuzumab. Trastuzumab was started with neoadjuvant chemotherapy and continued for a total of 1 year. pCR rates were significantly higher in the trastuzumab-chemotherapy arm (38% vs. 19%; p < .001). After a median follow-up time of 5.4 years the 5-year EFS was 58% (95% CI 0.48–0.66) in patients in the chemotherapy/trastuzumab group and 43% (95% CI 0.34–0.52) in those in the chemotherapy alone group; the unadjusted HR was 0.64 (95% CI 0.44–0.93; p = .016). There was a trend toward an OS benefit with hazard ratio of 0.66 (95% CI 0.43–1.01; p = .055). Of note, EFS survival was strongly correlated with pCR in patients given trastuzumab and only four cardiac events were considered to be drug related. These results indicate sustained benefit from neoadjuvant treatment with chemotherapy combined with trastuzumab in HER2 – positive LABC.

More recently dual HER2-targeted therapy with trastuzumab combined with pertuzumab or lapatinib has shown increased pCR rates for the treatment of HER2-positive breast cancer compared with single-agent HER2 blockade with trastuzumab ( Table 63.2 ). The NeoSphere trial was a randomized, phase II trial in which 417 women were randomly assigned to treatment with trastuzumab plus docetaxel every 3 weeks (arm A), or pertuzumab, trastuzumab plus docetaxel (arm B), or pertuzumab and trastuzumab (arm C) or pertuzumab plus docetaxel (group D). Patients given pertuzumab and trastuzumab plus docetaxel (arm B) had a significantly improved pCR rate compared with those given trastuzumab plus docetaxel (group A) (45.8% vs. 29%; p = .0141). These data demonstrate the increased efficacy of dual HER2-targeted therapy combined with chemotherapy.

The TRYPHANEA trial was a phase II trial in which 235 women with operable, inflammatory, or LABC were randomized to neoadjuvant treatment with six neoadjuvant cycles of FEC combined with trastuzumab and pertuzumab followed by docetaxel combined with trastuzumab and pertuzumab (arm A), FEC followed by docetaxel combined with trastuzumab and pertuzumab (arm B); or docetaxel plus carboplatin combined with pertuzumab and trastuzumab (arm C). The pCR rate was 61.6% (arm A), 57.3% (arm B), and 66.2% (arm C). During neoadjuvant treatment, two patients (2.7%; arm B) experienced symptomatic left ventricular systolic dysfunction and 11 patients (arm A: 4 [5.6%]; arm B: 4 [5.3%]; arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of 10% points or more from baseline to less than 50%. The TRYPHAENA study was designed as a cardiac safety study and no indication of greater cardiac toxicity was evident with dual HER2 targeting with pertuzumab and trastuzumab.

Lapatinib, an oral tyrosine kinase inhibitor that targets the HER1 and HER2 oncoproteins, has also improved pCR rates when combined with trastuzumab. In the phase III NeoALTTO trial patients with HER2-positive tumors measuring more than 2 cm were randomized to neoadjuvant treatment with trastuzumab, lapatinib, or the combination given for 6 weeks, then added to paclitaxel for 12 weekly infusions. A total of 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. The pCR rate was significantly higher in the group given lapatinib and trastuzumab than in the group given trastuzumab alone (51% vs. 30%, p = .0001). There was no significant difference in pCR rate between the lapatinib and the trastuzumab groups. No major cardiac dysfunction was reported. The frequency of grade 3 diarrhea was higher with lapatinib (23%) and lapatinib plus trastuzumab (21%) than with trastuzumab (2%). After surgery, all patients received adjuvant treatment with FEC followed by 34 weeks of the same assigned anti-HER2 therapy. At median event follow-up time of 3.7 years, there was no significant EFS or OS difference between the groups. Similarly, after 4.5 years of median follow-up, the adjuvant ALTTO study showed no difference in DFS with the combination of lapatinib and trastuzumab compared with trastuzumab alone. This phase III trial enrolled 8381 women who were randomized to adjuvant treatment with lapatinib combined with trastuzumab, lapatinib alone, trastuzumab followed by lapatinib or trastuzumab alone.

Similarly, the NSABP B-41 was a phase III trial in which all 529 patients were treated with AC followed by weekly paclitaxel. Concurrently with paclitaxel, patients were randomized to trastuzumab, lapatinib, or weekly trastuzumab plus lapatinib daily until surgery. Breast pCR rate was 53% in the trastuzumab group, 53% in the lapatinib group, and 62% in the combination group ( p = .095). The most common grade 3 toxicity was diarrhea occurring in 2% of patients in the trastuzumab group, 20% in the lapatinib group, and 27% in the combination group ( p < .0001). In the CALGB 40601 patients with HER2-positive stage II or III breast cancer had pCR rate of 56% when treated with 16 weeks of paclitaxel combined with lapatinib and trastuzumab compared with 46% when treated with trastuzumab and paclitaxel along ( p = .13).

Taken together these results suggest that neoadjuvant treatment of HER2-positive LABC should include dual HER2 blockade combined with chemotherapy to achieve the highest pCR. Lapatinib-based therapy is associated with higher rates of clinically important toxicities. However, current data do not demonstrate a survival benefit for the combination of trastuzumab with either pertuzumab or lapatinib.

Neoadjuvant Antiestrogen Therapy

The role of neoadjuvant antiestrogen therapy for patients with ER-positive and/or PR-positive cancers, large operable cancers, and LABC has been assessed in several studies, usually involving patients who were older and/or not felt to be candidates for neoadjuvant chemotherapy. Tamoxifen was first investigated as an alternative to surgery in elderly patients with large operable tumors with the goal of determining whether surgery could be avoided in a selected population of elderly patients. The results of the randomized studies of neoadjuvant tamoxifen alone versus surgery or neoadjuvant tamoxifen versus surgery plus tamoxifen conducted in elderly women not selected on ER-positive or PR-positive status are summarized in Table 63.3 . Local failure rates were higher in patients treated with tamoxifen alone, but none of the studies showed a benefit for surgery in decreasing the development of distant metastatic disease. These studies demonstrated that antiestrogen therapy is an effective alternative for elderly women with locally advanced disease who have a limited life expectancy and the results might have been more favorable for neoadjuvant endocrine therapy had the patient population been known to have tumors uniformly ER-positive.

TABLE 63.3

Randomized Clinical Trials of Neoadjuvant Tamoxifen Versus Surgery or Surgery and Tamoxifen

Study	Treatment	Study Population	Patient N	Local Failure (%)	Distant Failure (%)
Gazet et al.	Tamoxifen alone vs. surgery	Age >70 y, operable	200	25/38, p = ns	13/18, p = NS
Robertson et al. and Kenny et al.	Tamoxifen alone vs. wedge mastectomy	Age >70 y, operable	131	81/38, p < 0.001	24/19, p = NS
Fentiman et al.	Tamoxifen alone vs. modified radical mastectomy	Age ≥70 y, operable	164	62/11, p < 0.001	23/20, p = NS
Mustacchi et al.	Tamoxifen alone vs. surgery + tamoxifen	Age >70 y, operable	474	47/11, p < 0.001	22/25, p = NS
Bates et al.	Tamoxifen alone vs. surgery + tamoxifen	Age >70 y, operable	381	35/21	Not provided

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