Overview of the treatment of newly diagnosed, non-metastatic breast cancer

UpToDate, 2015


Introduction

Globally, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women. In the United States, breast cancer is the most commonly diagnosed cancer and the second most common cause of cancer death in women. In addition, breast cancer is the leading cause of death in women ages 40 to 49 years.

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology, which has been associated with a reduction in breast cancer mortality [1].

This topic will provide an overview of the initial treatment of breast cancer and posttreatment surveillance. The epidemiology, clinical manifestations, diagnosis, staging of breast cancer, and specific discussions of the multimodality treatments for early breast cancer and the approach to metastatic disease are discussed elsewhere.

Because ductal carcinoma in situ (DCIS) and invasive breast cancer are managed differently, we will restrict discussion in this topic to invasive breast cancer. A discussion on DCIS is covered separately.

Patient stratification

The vast majority of patients with newly diagnosed breast cancer in the United States and developed countries have no evidence of metastatic disease. For these patients, the treatment approach depends on the stage at presentation. For treatment purposes, breast cancer is characterized using the Tumor, Node, Metastases system (TNM) (table 1):

Early stage: This includes patients with clinical stage I, IIA, or a subset of stage IIB disease (T2N1).

Locally advanced: This includes a subset of patients with clinical stage IIB disease (T3N0) and patients with stage IIIA to IIIC disease.

Approximately 5% of patients will have simultaneous metastatic disease identified at the initial presentation (de novo stage IV breast cancer). The treatment approach to these patients is discussed separately.

Early-stage breast cancer

In general, patients with early-stage breast cancer undergo primary surgery (lumpectomy or mastectomy) to the breast and regional nodes with or without radiation therapy (RT). Following definitive local treatment, adjuvant systemic therapy may be offered based on primary tumor characteristics, such as tumor size, grade, number of involved lymph nodes, the status of estrogen (ER) and progesterone (PR) receptors, and expression of the human epidermal growth factor 2 (HER2) receptor.

Breast-conserving therapy

Breast-conserving therapy (BCT) is comprised of breast-conserving surgery (BCS, ie, lumpectomy) plus radiation therapy (RT). The goals of BCT are to provide the survival equivalent of mastectomy, a cosmetically acceptable breast, and a low rate of recurrence in the treated breast. BCT allows patients with invasive breast cancer to preserve their breast without sacrificing oncologic outcome. Successful BCT requires complete surgical removal of the tumor (with negative surgical margins) followed by moderate-dose RT to eradicate any residual disease.

Criteria that preclude BCT include

  • Multicentric disease
  • Large tumor size in relation to breast
  • Presence of diffuse malignant-appearing calcifications on imaging (ie, mammogram or magnetic resonance imaging [MRI])
  • Prior history of chest RT (eg, mantle radiation for Hodgkin disease)
  • Pregnancy
  • Persistently positive margins despite attempts at re-excision

For patients who desire BCT but are not candidates at the time of presentation, an alternative approach is the use of neoadjuvant therapy, which may allow for BCS without compromising survival outcomes.

Mastectomy  

A mastectomy is indicated for patients who are not candidates for BCT and those who prefer mastectomy.

Role of RT

Postmastectomy RT is indicated for patients at high risk for local recurrence, such as those with cancer involving the deep margins and pathologically involved axillary lymph nodes. If the likelihood of postmastectomy RT is high preoperatively, this may affect the choice of mastectomy type, the choice of the reconstructive approach, and optimal timing of the breast reconstruction (immediate versus delayed). Based upon the Early Breast Cancer Trialists’ Collaborative Group meta-analysis of 3786 women with invasive breast cancer undergoing an axillary dissection and mastectomy, there was a reduction in recurrences for node-positive women ([n = 1314, one to three nodes positive] and [n = 1772, four or more nodes positive]) undergoing postmastectomy radiation, but not for node-negative women [2].

Thus, preoperative coordination of care assures the best outcome. In many centers, this is accomplished by multi-disciplinary breast clinics. (See «Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer», section on ‘Patients treated with mastectomy’.)

Evaluation of the axillary nodes

The risk for metastases to the axillary nodes is related to tumor size and location, histologic grade, and the presence of lymphatic invasion within the primary tumor. Although internal mammary or supraclavicular nodes may be involved at the initial presentation, they rarely occur in the absence of axillary node involvement.

The evaluation of the regional nodes depends on whether axillary involvement is suspected prior to surgery:

For patients presenting with clinically suspicious axillary lymph nodes, a preoperative work-up including ultrasound plus fine needle aspiration (FNA) or core biopsy can help to determine the best surgical approach.

  • For patients with a positive biopsy, an axillary node dissection should be performed at the time of breast surgery.
  • For patients presenting with a negative biopsy, no further work-up is required prior to surgery. These patients should undergo a sentinel lymph node biopsy (SLNB) at the time of surgery.
  • Patients with a clinically negative axillary examination should undergo a SLNB at the time of surgery. Further evaluation of the regional nodes depends on the findings at SLNB.
  • Patients who have less than three pathologically involved sentinel nodes may not require a complete axillary node dissection [3]. However, whether or not patients with three or more pathologically involved sentinel nodes should undergo an axillary node dissection is best determined on an individualized basis, taking into account all other tumor risk factors and the patient’s performance status and comorbidities.

Adjuvant therapy

Systemic therapy refers to the medical treatment of breast cancer using endocrine therapy, chemotherapy, and/or biologic therapy.

Tumor characteristics predict which patients are likely to benefit from specific types of therapy. For example, hormone receptor-positive patients benefit from the use of endocrine therapy. In addition, patients with human epidermal growth factor receptor 2 (HER2)-positive cancers benefit from treatment using HER2-directed treatment.

For patients with early-stage breast cancer, treatment is based on tumor characteristics, patient status, and patient preferences:

  • Patients with hormone receptor-positive breast cancer should receive endocrine therapy. Whether they also should receive adjuvant chemotherapy depends on patient and tumor characteristics.
    • We offer chemotherapy to patients with early-stage hormone receptor-positive cancers that have high-risk characteristics, such as high-grade tumor, large tumor size (≥2 cm), pathologically involved lymph nodes, and/or high 21-gene recurrence score (≥31).
    • In the absence of high-risk features, we prefer not to administer chemotherapy.
  • For patients with ER/PR and HER2-negative disease (triple-negative breast cancer), we prefer to administer adjuvant chemotherapy if the tumor size is ≥0.5 cm. Because these patients are not candidates for endocrine therapy or treatment with HER2-directed agents, chemotherapy is their only option for adjuvant treatment, following or before radiotherapy. Patients with a triple-negative breast cancer <0.5 cm in size may forego adjuvant chemotherapy in most cases, due to minimal, if any, survival advantage.
  • Patients with HER2-positive breast cancer with a tumor size >1 cm should receive a combination of chemotherapy plus HER2-directed therapy. The management of small (≤1 cm) HER2-positive breast cancers is controversial.
  • Following chemotherapy, patients with ER-positive disease should also receive adjuvant endocrine therapy.

Locally advanced breast cancer

Locally advanced breast cancer is best managed with multimodality therapy employing systemic and locoregional therapy.

Neoadjuvant systemic therapy

Most patients with locally advanced breast cancer should receive neoadjuvant systemic therapy. The goal of treatment is to induce a tumor response before surgery and enable breast conservation.

Neoadjuvant therapy results in long-term distant disease-free survival and overall survival (OS) comparable to that achieved with primary surgery followed by adjuvant systemic therapy.

Our approach to the selection of treatment in the neoadjuvant setting is outlined below:

  • For most patients with hormone receptor-positive disease, we recommend chemotherapy in the neoadjuvant setting rather than endocrine therapy. Chemotherapy is associated with higher response rates in a shorter time period.
  • For patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, a HER2-directed agent (eg, trastuzumab with or without pertuzumab) should be added to the chemotherapy regimen.
  • We restrict endocrine therapy in the neoadjuvant setting to the treatment of postmenopausal patients with hormone receptor-positive disease who are not surgical candidates (regardless of tumor size) with a relative or absolute contraindication to chemotherapy (ie, significant medical comorbidities, advanced age, or poor performance status).

Surgical approach after neoadjuvant treatment

All patients should undergo surgery following neoadjuvant systemic therapy, even if they have a complete clinical and/or radiological response. In addition, patients who experience progression while on neoadjuvant systemic therapy should proceed with surgery, rather than switching the chemotherapy regimen.

Primary tumor

The choice between breast conservation and mastectomy after neoadjuvant treatment is dependent on the treatment response and patient characteristics (eg, breast size in relation to residual tumor size). Similar criteria used in the treatment of early-stage breast cancer are applied. However, patients who present with a large (ie, T4) breast lesion should undergo a mastectomy following neoadjuvant treatment.

Regional nodes

All patients require a surgical evaluation of the regional nodes following neoadjuvant treatment.

Primary surgery

Although some patients may be candidates for primary surgery at presentation, patients with locally advanced disease have an extremely high risk of local recurrence and distant metastases [4]. As a result, we prefer to treat patients with locally advanced breast cancer with neoadjuvant systemic therapy first.

For patients who proceed with primary surgery, based on pathological results, postoperative radiation therapy (RT) and adjuvant treatment should be administered.

Adjuvant therapy

The use of postoperative (adjuvant) systemic therapy is guided by the patient’s clinical status and tumor characteristics:

  • Patients who did not receive neoadjuvant systemic therapy should receive adjuvant treatment. The use of chemotherapy, biologic therapy, and/or endocrine therapy is guided by the same principles used to determine treatment for early-stage breast cancer.
  • For patients who received the full course of planned neoadjuvant chemotherapy
    • Patients with hormone receptor-positive breast cancer should receive endocrine therapy to reduce the risk of breast cancer recurrence and breast cancer-related mortality. There is no evidence that the addition of further chemotherapy in the form of adjuvant treatment improves OS. The selection of endocrine therapy is made according to menopausal status.
    • Patients with hormone receptor-negative breast cancer would typically not receive further chemotherapy in the adjuvant setting, as there is no evidence that the addition of adjuvant chemotherapy improves OS. These patients should begin posttreatment surveillance.

In some exceptional cases where the tumor progressed during neoadjuvant therapy or if the complete neoadjuvant therapy could not be delivered at the normal levels of intensity, adjuvant chemotherapy should be discussed and considered.

  • Patients with HER2-positive breast cancer should receive one year of trastuzumab following completion of surgery without the addition of further chemotherapy. This recommendation is based on studies of adjuvant chemotherapy with or without trastuzumab that demonstrated that the addition of one year of trastuzumab significantly improves disease-free survival and OS.

Patients treated with neoadjuvant endocrine therapy who undergo surgery should continue endocrine therapy in the adjuvant setting. Whether or not to administer adjuvant chemotherapy should be individualized.

Special considerations

Fertility preservation

Clinicians should discuss with patients the risk of infertility and possible interventions to preserve fertility prior to initiating potentially gonadotoxic therapy. This discussion should occur soon after diagnosis, since some interventions to preserve fertility take time and could delay the start of treatment. This is consistent with guidance from the American Society of Clinical Oncology [5]. The topic of fertility preservation is covered in detail separately.

Older women

For some patients with estrogen receptor (ER)-positive breast cancer, in whom surgery is not an option or life expectancy is limited, primary hormonal treatment with either tamoxifen or an aromatase inhibitor without surgery or radiation therapy (RT) can be used [6]. We prefer to individualize treatment based on the presence of medical comorbidities and patient and clinician preference.

Postmenopausal women

The topic of osteoclast inhibitors as a potential anticancer therapy in postmenopausal women is discussed separately.

Male breast cancer

The topic of male breast cancer is discussed separately.

Breast cancer in pregnancy

The treatment of breast cancer in pregnancy is discussed separately.

Prognosis

The majority of breast cancer recurrences occur within the first five years of diagnosis, particularly with hormone receptor-negative disease. However, some recurrences occur much later. In one study of patients with stage I, II, or III breast cancer who were without evidence of disease five years out from the original diagnosis, the recurrence risks in the subsequent five and ten years were still 11 and 19%, respectively [7].

Patients with early-stage breast cancer have a better prognosis than those patients diagnosed with locally advanced disease. According to Tumor, Nodes, Metastases (TNM) stage, five-year relative survival rates by stage for patients presenting with stage I, IIA, IIB, IIIA, IIIB, and IV disease were 95, 85, 70, 52, 48, and 18%, respectively [8]. Both younger (age <35 years) and older age (age ≥65 years) at diagnosis are associated with a worse prognosis [9,10].

Although there is some controversy regarding the prognosis of patients who present with synchronous breast cancer (ie, bilateral breast cancer diagnosed simultaneously), a recent study suggests their prognosis is no different from that of patients presenting with unilateral breast cancer [11].

The impact of multifocal (ie, invasive tumors identified within the same breast quadrant) or multicentric (ie, invasive tumors identified in separate breast quadrants) tumors on prognosis is controversial, with some evidence that they are associated with a poor prognosis [12] and other data suggesting they do not impact prognosis [13]. Currently, the TNM staging system does not assign independent value to multifocality or multicentricity and uses the diameter of the largest lesion to assign T stage.

Resumption of menses

For premenopausal patients who received adjuvant chemotherapy, chemotherapy-induced amenorrhea and lack of resumption of menstrual cycles after chemotherapy is associated with improved survival, after controlling for standard prognostic variables, particularly for hormone receptor-positive disease [14].

Posttreatment surveillance

Cancer survivors who have completed treatment for breast cancer should undergo regular follow-up. Annual mammography should also be performed in patients who underwent breast-conserving therapy (BCT). The routine use of breast magnetic resonance imaging (MRI) or whole-breast ultrasound is not recommended for breast cancer survivors because of a lack of evidence to inform their role in this population. In addition, laboratory tests and whole-body imaging in asymptomatic cancer survivors is not recommended.

Summary

Patient stratification

Patients with a new diagnosis of breast cancer can be stratified by their extent of disease:

  • Patients with clinical stage I, IIA, or a subset of stage IIB disease (T2N1) are classified as having early-stage breast cancer.
  • Patients with a T3 tumor without nodal involvement (T3N0, a subset of patients with clinical stage IIB disease) and those who present with stage IIIA to IIIC disease are classified as having locally advanced breast cancer.
  • Approximately 5% of patients will present with distant metastases (stage IV) at diagnosis.

Early-stage breast cancer

  • The surgical approach to the primary tumor depends on the size of the tumor, whether or not multifocal disease is present, and the size of the breast. The options include breast-conserving therapy (breast-conserving surgery plus radiation therapy [RT]) or mastectomy (with or without RT). Both approaches result in equivalent cancer-specific outcomes.
  • The risk for metastatic disease in the regional nodes is related to tumor size, histologic grade, and the presence of lymphatic invasion within the primary tumor. Although internal mammary or supraclavicular nodes may also be involved at the initial presentation, they rarely occur in the absence of axillary node involvement. The surgical approach to the regional nodes depends on the clinical status of the axilla:
    • For patients presenting with clinically suspicious axillary nodes, a preoperative work-up including ultrasound plus lymph node biopsy can help to determine the best surgical approach. If the lymph node biopsy is positive, an axillary node dissection should be performed. If the lymph node biopsy is negative, a sentinel lymph node biopsy (SLNB) at the time of surgery should be performed.
    • Patients who present with a clinically negative axilla do not require a preoperative work-up. These patients should undergo an SLNB at the time of definitive breast surgery. Patients who have <3 pathologically involved sentinel nodes by SLNB might not require an axillary node dissection. Whether or not patients with ≥3 pathologically involved sentinel nodes involved should undergo an axillary node dissection is best determined on an individualized basis, taking into account all other tumor risk factors and the patient’s performance status and comorbidities.
  • Tumor characteristics are used to select adjuvant treatment for patients with breast cancer.
    • Patients with hormone receptor-positive breast cancer should receive adjuvant endocrine therapy. The role of adjuvant chemotherapy in these patients requires a risk-stratified approach that takes into account patient and tumor characteristics to select patients who should receive adjuvant chemotherapy.
    • For patients with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)-negative disease (triple-negative breast cancer), we prefer to administer adjuvant chemotherapy if the tumor size is >0.5 cm.
    • Patients with HER2-positive breast cancer >1 cm in size should receive a combination of chemotherapy plus HER2-directed therapy. Following chemotherapy, patients with ER-positive disease should also receive adjuvant endocrine therapy.

Locally advanced breast cancer

  • Most patients with locally advanced, inoperable breast cancer should receive neoadjuvant systemic therapy rather than proceeding with primary surgery. These patients are usually not candidates for breast conservation at their initial presentation. Neoadjuvant treatment improves the rate of breast conservation without compromising survival outcomes.
    • For most patients, we recommend chemotherapy in the neoadjuvant setting rather than endocrine therapy. Chemotherapy is associated with higher response rates in a faster time frame. A HER2-directed agent (ie, trastuzumab) should be added to the chemotherapy regimen for tumors that are HER2-positive.
    • We restrict endocrine therapy in the neoadjuvant setting to the treatment of postmenopausal patients who are not surgical candidates at the time of presentation and have a relative or absolute contraindication to chemotherapy (ie, significant medical comorbidities, advanced age, or poor performance status).
  • Following surgery (with or without neoadjuvant systemic therapy), all patients who undergo breast-conserving surgery should undergo adjuvant RT to maximize locoregional control.
  • Some patients treated by a mastectomy should receive postmastectomy RT. The administration of adjuvant RT should be based upon the original pretreatment stage, regardless of the pathologic response to neoadjuvant therapy.
  • The use of chemotherapy, biologic therapy, and/or endocrine therapy is guided by the same principles used to determine treatment for early-stage breast cancer.
  • For patients who received neoadjuvant chemotherapy:
    • Patients with hormone receptor-positive breast cancer should receive adjuvant endocrine therapy. The selection of endocrine therapy is made according to menopausal status.
    • Patients with hormone receptor-negative breast cancer should not receive further treatment provided they completed the planned neoadjuvant chemotherapy regimen. These patients should begin posttreatment surveillance.
    • Patients with hormone receptor-negative breast cancer who did not complete planned neoadjuvant treatment prior to surgery are candidates for further chemotherapy in the postoperative (or adjuvant) setting.
    • Patients with HER2-positive breast cancer should receive one year of trastuzumab following completion of surgery.
  • Patients treated with neoadjuvant endocrine therapy who undergo surgery should continue endocrine therapy in the adjuvant setting. Whether or not to administer adjuvant chemotherapy should be individualized.
  • For some patients with ER-positive breast cancer, in whom surgery is not an option or life expectancy is limited, primary hormonal treatment with either tamoxifen or an aromatase inhibitor without surgery can be used.

References

  1. Kesson EM, Allardice GM, George WD, et al. Effects of multidisciplinary team working on breast cancer survival: retrospective, comparative, interventional cohort study of 13 722 women. BMJ 2012; 344:e2718.
  2. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014; 383:2127.
  3. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011; 305:569.
  4. Haagensen CD, Stout AP. CARCINOMA OF THE BREAST: II. CRITERIA OF OPERABILITY. Ann Surg 1943; 118:859.
  5. Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006; 24:2917.
  6. Hamaker ME, Bastiaannet E, Evers D, et al. Omission of surgery in elderly patients with early stage breast cancer. Eur J Cancer 2013; 49:545.
  7. Brewster AM, Hortobagyi GN, Broglio KR, et al. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst 2008; 100:1179.
  8. Newman LA. Epidemiology of locally advanced breast cancer. Semin Radiat Oncol 2009; 19:195.
  9. Bastiaannet E, Liefers GJ, de Craen AJ, et al. Breast cancer in elderly compared to younger patients in the Netherlands: stage at diagnosis, treatment and survival in 127,805 unselected patients. Breast Cancer Res Treat 2010; 124:801.
  10. van de Water W, Markopoulos C, van de Velde CJ, et al. Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer. JAMA 2012; 307:590.
  11. Nichol AM, Yerushalmi R, Tyldesley S, et al. A case-match study comparing unilateral with synchronous bilateral breast cancer outcomes. J Clin Oncol 2011; 29:4763.
  12. Weissenbacher TM, Zschage M, Janni W, et al. Multicentric and multifocal versus unifocal breast cancer: is the tumor-node-metastasis classification justified? Breast Cancer Res Treat 2010; 122:27.
  13. Lynch SP, Lei X, Chavez-MacGregor M, et al. Multifocality and multicentricity in breast cancer and survival outcomes. Ann Oncol 2012; 23:3063.
  14. Swain SM, Jeong JH, Geyer CE Jr, et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med 2010; 362:2053.

 

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