Surgical Procedures for Advanced Local and Regional Malignancies of the Breast

Introduction

As recent as the early 2000s, locally advanced breast cancer (LABC) carried a grim prognosis, and surgery was thought to play a more palliative role in its management. However, in more recent years, the understanding of the disease process has led to new systemic therapies that have transformed the role of surgery in this particular patient population. These targeted therapies have provided key information regarding the tumor response when administered in the neoadjuvant setting and have led to downstaging of the patient’s disease, thus converting the once inoperable patient into an operable candidate. Increasingly, surgery is becoming an integral part in the multidisciplinary management of LABC.

Staging System Revisions and Implications

LABCs account for 10% to 15% of all newly diagnosed breast cancers, and they include tumors that are large with skin or chest wall invasion or have extensive regional lymph node involvement, with no evidence of distant metastasis on initial presentation. Patients with LABC have higher rates of local and distant relapse resulting in worse survival outcomes compared with patients with early-stage breast cancer. The term locally advanced breast cancer encompasses a heterogeneous group of breast neoplasms: locally recurrent (persistent) breast carcinoma, inflammatory breast carcinoma (T4d), and clinical stage IIIA, IIIB, and IIIC breast carcinomas, all of which have varying degrees and locations of lymph node involvement and some of which involve extension of cancer to the chest wall and/or skin ( Fig. 54.1 ). Inflammatory and locally recurrent carcinomas are distinct biologic entities that are discussed elsewhere in this book.

Fig. 54.1, Patient with locally advanced breast cancer involving the nipple-areola complex. Note the prominent skin retraction and nipple distortion caused by a large underlying primary tumor.

In 2010 the American Joint Committee on Cancer (AJCC) published the 7th edition of the Breast Cancer Staging Manual, which reflected the knowledge gained from improved and evolving application of sentinel lymph node biopsy (SLNB), immunohistochemistry, molecular techniques, improved imaging modalities including magnetic resonance imaging (MRI), and the results of clinical trials. The 8th edition of the AJCC staging system was published in 2018 and incorporated prognostic biomarkers to aid in predicting clinical outcomes and treatment response on a more individualized basis. These prognostic markers included tumor grade, HER2, estrogen receptor (ER), and progesterone receptor (PR) status, and genomic assays (Oncotype DX). The increasingly refined assessment of both nodal involvement and breast cancer subtype are reflected in the updated staging system, which allows clinicians to provide more personalized treatment plans for patients presenting with LABC.

Pretreatment Evaluation, Diagnosis, and Management

Establishing a tissue diagnosis is a priority for patients presenting with LABC. After thorough breast imaging, which includes bilateral diagnostic mammography and ultrasonography of the breast and nodal basins, core needle biopsy of the primary tumor should be performed to provide tissue for histopathologic examination and determination of hormone receptor status and HER2/neu expression. If breast-conserving surgery (BCS) is being considered, a clip should be placed into the primary tumor site before initiation of any systemic therapy. Matted, fixed, or sonographically suspicious axillary, supraclavicular, infraclavicular, and internal mammary lymph nodes should be subjected to fine-needle aspiration (FNA) biopsy for more definitive staging by radiologists with the expertise to perform this procedure accurately and safely. Core needle biopsy can also be performed and may be preferred when cytologic expertise is not available ( Fig. 54.2 ). A clip or marker should also be placed at the site of any biopsy-proven metastatic axillary lymph nodes for future treatment planning.

Fig. 54.2, (A) Ultrasound of the axilla showing an abnormal node with cortical thickening. (B) Fine-needle aspiration smear of the same lymph node shows benign lymphoid tissue. (C) The patient underwent a sentinel node biopsy, which demonstrated a metastatic focus.

A complete staging workup includes a thorough history and physical examination, a complete blood cell count with differential and platelet counts, a biochemical survey (i.e., comprehensive metabolic panel including electrolytes and liver enzymes), and imaging for distant disease including a bone scan as well as chest and abdominal cross-sectional imaging. Findings suspicious for metastatic disease should be verified histologically through biopsy wherever possible. Each patient should be evaluated in a multidisciplinary context with a team including surgical, medical, and radiation oncologists; radiologists; pathologists; and plastic surgeons. A consensus treatment plan should be presented to the patient initially and should be reviewed throughout the course of treatment in the context of response to neoadjuvant systemic therapy as well as postoperatively to review pathologic analysis of the surgical specimens.

Treatment Approaches for Locally Advanced Breast Cancer

As with early-stage breast cancer, the most important outcomes used to assess treatment efficacy in patients with LABC are locoregional control and survival.

Historical Management of Locally Advanced BreastCancer

Surgery is the oldest treatment for breast cancer, but enthusiasm for radical surgical resections has waxed and waned over the years. At the end of the 19th century, William Halsted described the radical mastectomy, which involved removal of the entire breast with en bloc removal of all axillary lymphatics, the chest wall musculature, and part of the sternum and ribs if they were involved with tumor. Despite this aggressive approach to locally advanced tumors, survival rates remained poor, ranging from 13% to 20% at 5 years.

Awareness of variations in biology (and therefore the effectiveness of therapy) of LABC stems from Haagensen and Stout’s pioneering insights derived from nearly 30 years of cumulative experience in breast cancer management. On review of 1135 breast cancer patients treated with radical mastectomy at Presbyterian Hospital in New York from 1915 to 1942, these authors observed that patients with certain features of LABC were beyond cure, even with radical surgery. Haagensen’s “grave signs” included edema of the skin of the breast, skin ulceration, chest wall fixation, an axillary lymph node greater than 2.5 cm in diameter, and fixed axillary nodes. Patients with two or more of these signs had a 42% local recurrence rate and a 5-year disease-free survival rate of only 2%.

McWhirter and colleagues demonstrated that less disfiguring surgery produced results similar to those seen with the more aggressive radical mastectomy, an idea that led to the recognition that treatment failure from breast cancer stemmed from systemic dissemination before surgery. The Alabama Breast Project examined the efficacy of modified radical mastectomy versus radical mastectomy. Although no significant difference was seen in survival between the two groups after a median follow-up of 10 years, despite higher recurrence rates in the modified radical mastectomy group, there was a subset of patients with more advanced cancers who had improved survival with radical mastectomy. The Alabama experience further supported the importance of exploring whether multimodal therapy might yield survival rates similar to those of radical mastectomy without the severely morbid sequelae of radical surgical interventions.

Experiences with unimodal therapy demonstrated that good local control rates achieved with surgery or radiotherapy alone did not translate to improved prognosis and long-term survival, as hematogenous metastases could not be treated with local therapy alone. Consequently, by the late 1970s, systemic chemotherapy was an integral part of the primary management of LABC, a development that occurred in large part as a result of several major prospective multimodal trials including the National Cancer Institute, Milan, Italy trials in 1973 and 1975 andan MD Anderson Cancer Center trial in 1974 (online Appendix, Historical Trials ). These trials set the stage for the multimodal approach to the management of LABC, which over the years has progressed to include neoadjuvant and adjuvant chemotherapy, radiation therapy, endocrine therapy, and targeted therapies.

Neoadjuvant Therapy in LABC

Neoadjuvant therapy has become a key component in the management of LABC. In addition to providing real-time assessment of response, which is informative for long-term prognosis, downsizing of local regional disease through neoadjuvant chemotherapy can potentially impact the surgical approach to patient care.

Chemotherapy

Neoadjuvant chemotherapy is an important component in the management of LABC. Although randomized trials have demonstrated that neoadjuvant chemotherapy and adjuvant chemotherapy are associated with similar recurrence-free and overall survival rates when the same regimen is applied, neoadjuvant treatment nevertheless has many advantages over adjuvant therapy with regards to LABC.

Neoadjuvant chemotherapy can (1) convert LABC from inoperable to operable, (2) increase the rate of BCS, (3) serve as an in vivo chemosensitivity test for a given tumor, and (4) allow earlier treatment of micrometastatic disease. Pathologic response to neoadjuvant systemic therapy in the breast and lymph nodes correlates with patient survival. There was initially concern that a potential disadvantage was the loss of prognostic information provided by tumor size and nodal status in an untreated surgical specimen, but it has been shown that patients who have a complete clinical or pathologic response with neoadjuvant chemotherapy have improved overall and disease-free survival. Multiple large, randomized trials have proven the safety of neoadjuvant chemotherapy in LABC and have shown objective response rates ranging from 60% to 80%.

The tumor response to neoadjuvant chemotherapy in patients with LABC depends on the agents or combination of agents used ( Box 54.1 ). Randomized trials have confirmed the superiority of anthracycline-based regimens over cyclophosphamide, methotrexate, and 5-fluorouracil in the treatment of early, locally advanced, and metastatic breast cancer. The rates of pathologic complete response (pCR) to neoadjuvant systemic therapy were initially reported to range from 6% to 15% with anthracycline-based regimens to almost 30% with the addition of a taxane. More contemporary studies have demonstrated higher pCR rates as regimens have been modified to specific breast cancer subtypes ( Table 54.1 ). (online Appendix, Neoadjuvant Chemotherapy ).

Box 54.1 MD

Anderson Neoadjuvant and Adjuvant Chemotherapy Protocols

AC , Adriamycin (doxorubicin) 60 mg/m ² IV + Cytoxan (cyclophosphamide) 600 mg/m ² IV; G-CSF , granulocyte colony stimulating factor; IV , intravenous; Paclitaxel , 80 mg/m ² IV weekly; TC , Taxotere (docetaxel) 75 mg/m ² IV + Cytoxan (cyclophosphamide) 600 mg/m ² IV; TCHP , Taxotere (docetaxel) 75 mg/m ² IV + carboplatin AUC (area under the curve) 6 mg/mL IV + Herceptin (trastuzumab) 8 mg/kg IV loading followed by 6 mg/kg IV maintenance + Perjeta (pertuzumab) 840 mg IV loading followed by 420 mg IV maintenance; THP , Taxotere (docetaxel) 75 mg/m ² IV + Herceptin (trastuzumab) 8 mg/kg IV loading followed by 6 mg/kg IV maintenance + Perjeta (pertuzumab) 840 mg IV loading followed by 420 mg IV maintenance.

Regimens for HER2-Nonamplified Disease

Paclitaxel × 12 weekly cycles followed by AC × 4 cycles (administered either as dose-dense every 2 weeks w/G-CSF support or every 3 weeks)
TC × 4 cycles (administered every 3 weeks) with G-CSF support

Regimens for HER2-Amplified Disease

AC × 4 cycles (administered every 3 weeks) followed by THP × 4 cycles (continuation of trastuzumab to complete 1 year of therapy)
TCHP × 6 cycles (administered every 3 weeks with continuation of trastuzumab to complete 1 year of therapy)

Table 54.1

Clinical Trials Examining Neoadjuvant Protocols and Associated Rates of pCR

Trial	Population	Regimen: pCR Rate	Comments
NSABP B-27	802 patients 31% clinically node-positive (N1), T1c–T3	AC → T: 26%
TRYPHAENA	225 patients Locally advanced/operable or inflamma-tory HER2+ breast cancer	TCHP × 6 cycles (n = 76): 47.5% in the HR+ subgroup (and 81.1% in the HR− subgroup FEC × 3 cycles → THP × 3 cycles (n = 75): 45.7% in the HR+ subgroup, 62.5% in the HR− subgroup
NeoSphere	417 patients Locally advanced/operative or inflam-matory HER2+ breast cancer, primary tumor >2 cm	THP × 4 cycles (n = 107): 39.3% (treated with FEC × 3 cycles postoperatively)
GEPARTRIO	2090 patients with untreated breast cancer, of which 1390 responders randomized to receive four or six additional cycles	TAC × 8 cycles (n = 704) with clinical response of >50% reduction after initial two cycles): 23.5% TAC × 6 cycles (n = 686, with clinical response <50% after initial two cycles): 21%	pCR by subgroup: Age <50 years: 26.4% Age ≥50 years: 17.5% Ductal histology: 24% Lobular histology: 10.2% Grade 3: 31.5% Grade 1–2: 15.4% LN+: 23.4% LN−: 21.5% ER/PR−: 43.2% Other: 10% HER2+: 20.6%

AC → T , Adriamycin (doxorubicin) + Cytoxan (cyclophosphamide) followed by Taxotere (docetaxel); ER , estrogen receptor; FEC , 5-fluorouracil + epirubicin + Cytoxan (cyclophosphamide); HER2+ , HER2/neu-amplified; HR , hormone receptor; LN , lymph node; pCR , pathologic complete response; PR , progesterone receptor; TAC , Taxotere (docetaxel) + Adriamycin (doxorubicin) + Cytoxan (cyclophosphamide); TCHP , Taxotere (docetaxel) + Carboplatin + Herceptin (trastuzumab) + Perjeta (pertuzumab); THP , Taxotere (docetaxel) + Herceptin (trastuzumab) + Perjeta (Pertuzumab).

A series of trials out of Germany, entitled the Gepar trials, have evaluated the pCR rates in breast cancer patients using different combinations and doses of systemic therapies comparative to standard neoadjuvant chemotherapy. As new agents are developed, the Gepar studies have incorporated them in their study protocols. For example, GeparSepto demonstrated that nanoparticle albumin-bound (NAB)-paclitaxel administered weekly significantly improved pCR rates when compared to weekly solvent-based paclitaxel, epirubicin, and cyclophosphamide in the neoadjuvant setting (38% vs. 29%, respectively, P <0.005). GeparNuevo added the immune-checkpoint inhibitor durvalumab to standard neoadjuvant chemotherapy in primary triple-negative breast cancer (TNBC) and found improved pCR rates (53.4% in treatment group vs. 44.2% in placebo, P =0.287), though this was not statistically significant.

Similarly, the well-known National Surgical Adjuvant Breast and Bowel Project (NSABP) series of clinical trials included studies evaluating the effect of different treatment regimens administered in the neoadjuvant setting. NSABP B-27 is included in Table 54.1 and found a pCR rate of 26% in breast cancer patients treated with preoperative AC followed by docetaxel when compared to neoadjuvant AC alone or neoadjuvant AC followed by adjuvant docetaxel. NSABP B-40 was a randomized phase III trial evaluating pCR rates with the addition of capecitabine or gemcitabine to docetaxel before AC with or without bevacizumab. The addition of bevacizumab increased the pCR rate from 28.2% to 34.5% ( P =0.02).

A multinational phase III, double-blind, placebo-controlled randomized clinical trial entitled the BrighTNess trial evaluated women with operable clinical stage II and III TNBC who were randomized to receive one of three different treatment regimens. The primary end point was pCR; however, a secondary end point was the rate of conversion from BCS ineligible to BCS eligible. They found that neoadjuvant systemic therapy increased those eligible for BCS from 76.5% at time of diagnosis to 83.8% after treatment. Similar results were observed in the CALGB 40603 trial, which was a randomized phase II trial evaluating patients with stage II or III TNBC who received neoadjuvant paclitaxel with or without carboplatin and/or bevacizumab, followed by doxorubicin and cyclophosphamide. In this trial 42% of patients ineligible for BCS converted to BCS eligible after neoadjuvant therapy, with an increase in absolute BCS eligibility rate from 54% to 68%.

Endocrine Therapy

Endocrine therapy is a critical component of multimodal care for patients with hormone receptor–positive breast cancer. Endocrine therapy is increasingly used in the neoadjuvant setting and has been demonstrated to result in significant increases in breast conservation rates and improved postsurgical outcomes in patients with stage II and III ER-positive breast cancer. pCR rates are low compared with those observed in other breast cancer subtypes; however, the Preoperative Endocrine Prognostic Index (PEPI score; Ki67 proliferation index, tumor size, nodal status and ER status after endocrine therapy) is a reliable predictor of prognosis after treatment with neoadjuvant endocrine therapy. Endocrine therapy is typically administered for 3 to 4 months before assessing treatment response. In a phase III randomized trial in postmenopausal women, aromatase inhibitors, such as letrozole, had better efficacy compared with tamoxifen. In the phase II American College of Surgeons Oncology Group (ACOSOG) Z1031 trial, anastrozole, letrozole, and exemestane all demonstrated similar efficacy in the neoadjuvant setting for postmenopausal patients with ER-positive disease (online Appendix, Neoadjuvant Endocrine Therapy ).

Targeted Therapy

The development of anti-HER2 targeted therapy has transformed HER2/neu-amplified (HER2-positive) breast cancer from a disease with a poor prognosis to an opportunity for improved survival and potential for cure. Multiple trials have now demonstrated improved rates of BCS, pCR, and survival when neoadjuvant trastuzumab is administered in conjunction with standard chemotherapy regimens. Lapatinib has also been found to be effective in the treatment of HER2-positive breast cancer but has side effects that are generally more severe than those seen with trastuzumab. More recently, pertuzumab, initially shown to improve progression-free survival in metastatic breast cancer patients in the CLEOPATRA trial, has emerged as a powerful adjunct to trastuzumab and docetaxel in the treatment of HER2-positive breast cancer. TRYPHAENA and NEOSPHERE are both randomized phase II trials that have demonstrated the efficacy of pertuzumab in improving rates of pCR in HER2-positive LABC with low cardiac toxicity when administered in conjunction with trastuzumab and docetaxel. The combination of anti-HER2 targeted therapy with endocrine therapy is currently being assessed in the neoadjuvant setting. NSABP B-52 is an actively accruing phase III trial evaluating pCR in patients with HER2-positive large operable breast cancer and LABC treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) with and without estrogen deprivation (aromatase inhibitor plus ovarian function suppression in premenopausal women or an aromatase inhibitor in postmenopausal women).

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