Perioperative Care of the Cancer Patient: Breast Procedures

Background

In the United States breast cancer is the most commonly diagnosed cancer in women and accounts for over 260,000 new cases each year. A woman living in the United States has a 12% lifetime risk of being diagnosed with breast cancer. Although mortality rates have been declining, it is the second most common cause of death in women and responsible for over 40,000 deaths.

Risk Factors

Multiple risk factors are associated with breast cancer development. Increased exposure to estrogen is associated with an elevated risk of developing breast cancer, whereas reducing exposure is thought to be protective. Correspondingly, factors that increase the number of menstrual cycles such as early menarche, nulliparity, older age at first pregnancy, and late menopause are associated with increased risk. Additionally, obesity is associated with long-term heightened exposure to estrogen. Nonhormonal risk factors include older age, family history, genetic predisposition, and radiation exposure (particularly mantle radiation during adolescence). Seventy-five percent of breast cancer cases occur in patients aged >50 years. A family history of breast cancer, particularly in a first-degree relative, increases the risk twofold in the case of one affected relative, and up to fourfold in the case of more than one affected relative compared to women without a family history.

Five to ten percent of breast cancers are caused by inheritance of germline mutations in genes such as BRCA1 and BRCA2. Compared to women in the general population, BRCA1 and BRCA2 mutation carriers are estimated to have as high as 70% risk of developing breast cancer by the age of 80 years. Other inherited conditions associated with an increase in breast cancer risk include Li-Fraumeni and Cowden syndromes. ^, Lobular carcinoma in situ (LCIS) is characterized by abnormal cell growth within and expanding the terminal duct lobular units. Women with LCIS are 7 to 12 times more likely to develop invasive cancer in either breast compared to women without LCIS, with 65% of those being ductal in origin. As such, LCIS is generally not thought to be a precursor for invasive cancer but regarded as a strong marker of increased risk.

Screening

The American Cancer Society (ACS) recommendations for the early detection of breast cancer vary depending on a woman’s age and underlying risk factors. Screening modalities include mammography and magnetic resonance imaging (MRI) for women who are at high risk. For women at average risk of developing breast cancer, the ACS recommends that women 40 to 44 years of age have the option to begin annual mammography, those aged 45 to 54 years should undergo annual mammography, and those aged 55 years and older may transition to biennial mammography or continue to have the option of annual mammograms. Furthermore, women should continue breast cancer screening as long as their overall health is good, and they have a life expectancy of 10 years or more. For women with a high lifetime risk (∼20%–25%) of breast cancer, recommendations include an annual screening MRI in addition to mammography beginning at 30 years of age.

Staging

All patients diagnosed with breast cancer should be assigned a clinical stage based on the involvement of the breast and/or nodal regions. Staging allows for efficient identification/guidance of local and systemic therapy options and provides baseline prognostic information for patients and providers. TNM is an internationally accepted system used to determine the disease stage. The TNM classification uses information on tumor size and local spread (T), the extent of spread to nearby lymph nodes (N), the presence or absence of distant metastases (M), and additional biological factors. ^, A breast cancer stage of 0–IV is assigned, ranging from locally contained disease to advanced disease.

Types of Breast Cancers

Breast cancer cells are considered to be in situ or invasive depending on whether they invade the basement membrane. Ductal carcinoma in situ (DCIS) is characterized by abnormal proliferation of the epithelium that lines the milk ducts. Approximately 20% of breast cancer cases diagnosed in the United States are DCIS. There is a significant risk (nearly fivefold) of invasive breast cancer in women with DCIS. Invasive cancer is usually observed in the ipsilateral breast, suggesting that DCIS is an anatomic precursor for more invasive diseases.

Although invasive breast cancer is generally referred to as a single disease, there are several distinct histologic subtypes and at least four different molecular subtypes that differ in terms of risk factors, presentation, response to treatment, and outcomes. ^, Invasive ductal carcinoma accounts for approximately 70%–80% of invasive lesions. This type of carcinoma presents with macroscopic or microscopic axillary lymph node metastases in up to 25% of screen-detected cases and 60% of symptomatic cases. Invasive lobular carcinoma accounts for approximately 8% of all breast cancers. The histopathologic features of this cancer include small cells that infiltrate the mammary stroma and adipose tissue individually and in a single-file pattern. Mixed histology, comprising both ductal and lobular characteristics, occurs in approximately 7% of invasive cancers. Other histologic subtypes include mixed, medullary, papillary, tubular, and mucinous, which account for less than 5% of invasive breast cancers.

Routine identification of the presence or absence of specific hormones or growth factor receptors is utilized in gene profiling. Hormone (estrogen [ER] or progesterone [PR]) receptors, excess levels of human epidermal growth factor receptor 2 (HER2), and/or extra copies of the HER2 gene (HER2+/HER2−) are routinely identified in invasive cancers. Molecular subtypes are identified based on these analyses. The main types include luminal, HER2-enriched, and basal.

Prognosis

The prognosis of patients depends on the stage of the tumor at the time of diagnosis. Influencing factors include tumor size, histologic grade, axillary lymph node status, and hormone receptor status. The majority of breast cancer recurrences occur within the first 5 years of diagnosis, particularly with hormone receptor-negative disease. The overall 5-year relative survival rate is 99% for localized disease, 85% for regional disease, and 27% for distant-stage disease.

Future Aims in the Approach to Breast Cancer

Up to 50% of women in the United States will consult a surgeon about breast disease at some point in their lives. Twenty-five percent of women will undergo breast biopsy for the diagnosis of an abnormality, and 12% will develop some variant of breast cancer. Considerable progress has been made in the integration of surgery, radiation therapy, and systemic therapy to control local-regional disease, enhance survival, and improve the quality of life (QoL) of breast cancer survivors. Potential areas for further research and improvement in breast cancer include: (1) increasing patient access to education regarding breast cancer treatment options with the goal of improving decision-making, (2) health-related quality of life (HR-QoL) outcomes research, (3) prompt dissemination and adoption of new treatment options, and (4) strategies to curb the rising costs of health care for patients. ^,

In the next section we present an overview of the medical and surgical management of the breast cancer patient.

Management of the Breast Cancer Patient

Nonsurgical Management of Breast Cancer

Systemic Treatment

Systemic therapy refers to the medical treatment of breast cancer using endocrine therapy, chemotherapy, and/or biologic therapy prior to or following definitive local treatment. To determine the risk of recurrence and the effectiveness of systemic therapy, one must assess factors, such as age, life expectancy, comorbidities, pathologic findings in the breast and axilla, and biological behavior of the tumor. Systemic therapy may be offered based on primary tumor characteristics, such as tumor size, grade, number of involved lymph nodes, status of ER and PR receptors, and expression of HER2 receptor.

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy is utilized in cases of locally advanced and potentially inoperable breast cancer to render the disease amenable to resection. Clinical criteria for inoperability include inflammatory carcinoma, tumors that are fixed to the bony chest wall (e.g., ribs and sternum), extensive skin involvement with ulceration or satellite skin nodules, fixed or matted axillary lymphadenopathy, involvement of neurovascular structures of the axilla, or lymphedema of the ipsilateral arm. In these cases, systemic therapy may be administered as an initial treatment to reduce tumor burden and will subsequently improve the rate of operability to 80%. Neoadjuvant chemotherapy is also used in cases of operable tumors to downstage disease in the breast and axilla. This may facilitate breast conservation surgery (BCS), improve cosmetic outcome, and in some instances allow patients to avoid axillary lymph node dissection (ALND) and the associated morbidity with this procedure. Last, neoadjuvant therapy may be utilized in women who may have a temporary contraindication to surgery such as women diagnosed with breast cancer during pregnancy.

Chemotherapy remains the standard neoadjuvant approach in most patients, including those with hormone receptor-positive disease; however, endocrine therapy may be used in a certain subset of these patients. For patients with HER2-positive breast cancer, a HER2-directed agent (i.e., trastuzumab with or without pertuzumab) is typically administered in addition to the chemotherapy regimen. For patients with hormone receptor-negative and HER2-negative disease, neoadjuvant therapy consists of chemotherapy alone. Overall, in selected patients, neoadjuvant therapy reduces the rate of axillary lymph node metastases, increases the rate of breast conservation, and has comparable long-term disease-free survival and overall survival compared to patients undergoing primary surgery followed by adjuvant systemic therapy. ^,

Adjuvant Chemotherapy

Generally, adjuvant chemotherapy is indicated for patients with triple-negative breast cancer and either a tumor size >0.5 cm or pathologically involved lymph nodes (regardless of tumor size). Common regimens utilized for HER2-negative disease include anthracycline-based regimens such as doxorubicin and cyclophosphamide. These are typically administered for four cycles of dose-dense treatment (every 2 weeks) followed by paclitaxel administered either weekly for 12 weeks or every 2 weeks for four cycles. With the use of an anthracycline-containing regimen compared with no treatment, there is a reduction in the risk of recurrence from 47% to 39%. Furthermore, breast cancer mortality also decreases from 36% to 29% and overall mortality from 40% to 35%, respectively.

Meta-analyses have demonstrated the benefits of adjuvant chemotherapy in reducing recurrence and breast cancer mortality. There is a greater magnitude of benefit in those with HR-negative disease (21%–25% relative risk reduction) compared to those with HR-positive disease (8%–12%). ^, For patients with HR-positive and node-negative breast cancer, Oncotype DX provides an estimate of chemotherapy benefit. Patients with high Oncotype recurrence scores (≥31) have a large reduction in risk of recurrence with chemotherapy, while those with low scores derive minimal if any benefit from chemotherapy. Chemotherapy for patients in this group may consist of either anthracycline-containing or anthracycline-sparing regimens. In patients with low Oncotype recurrence scores, endocrine therapy alone is sufficient, as these patients have a favorable outcome with a 5-year overall survival of 98% with endocrine therapy alone.

HER2-Directed Therapy

Approximately 20% of patients with early breast cancer have tumors that exhibit overexpression, amplification, or a combination of these characteristics of the HER2 receptor or oncogene. Adjuvant HER2-targeted therapy (trastuzumab and/or pertuzumab) is now the standard of care for these patients. Several large trials have demonstrated that a year of adjuvant trastuzumab after chemotherapy reduces recurrence (about 50%) and increases 10-year disease-free survival (9%) in patients with this type of early breast cancer.

Endocrine Therapy

Hormone receptor-positive breast cancer represents the vast majority of breast cancers around the world; approximately 60%–75% of women with invasive breast cancer are ER-positive and 65% are PR-positive. Endocrine therapy is recommended for most patients with hormone-positive disease. Patients may be treated with endocrine therapy for 5–10 years and possibly longer, as a longer duration of therapy may confer additional benefits. If women are pre- or perimenopausal or if menopausal status is unknown, they should be offered tamoxifen for a total duration of 10 years. Aromatase inhibitors (anastrozole, letrozole, and exemestane) are used in postmenopausal women but may also be prescribed sequentially with tamoxifen. Adjuvant tamoxifen reduces the risk of recurrence by nearly 50% during years 0–4 with continued risk reduction of over 30% in years 5–9. ^, Furthermore, after 5 years of tamoxifen treatment, an additional 5 years of aromatase inhibitors provides an additional 40% relative risk reduction in recurrence.

Surgical Management of Breast Cancer

Breast-conserving Therapy

Successful breast-conserving therapy (BCT) entails complete, cosmetically acceptable surgical removal of the tumor (lumpectomy with negative surgical margins defined as no ink on tumor) followed by radiotherapy (RT) to eradicate any residual disease. Among women with operable breast cancer, randomized trials have demonstrated equivalent disease-free and overall survival between mastectomy and BCT. Advances in neoadjuvant therapy, surgical and radiation therapy techniques, and pathologic assessment of the tumor have increased patient eligibility for this approach. Inability to obtain adequate surgical margins or patient intolerance of adjuvant RT may preclude BCT. Additional contraindications include inflammatory breast cancer, multicentric disease, diffuse malignant microcalcifications on mammography, prior history of chest RT, pregnancy, and connective tissue disease (i.e., scleroderma or lupus erythematosus). ^,

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