A 33-year-old woman presents to the outpatient clinic for the evaluation of a painless breast mass that has been slowly enlarging over the past 3 months. Her past medical history is unremarkable. She has no prior history of breast complaints or trauma. The findings from the physical examination are unremarkable except for the breast examination. A hard, nontender 3-cm mass is noted in the upper outer quadrant of her left breast. The left axilla is without abnormalities. Examination of the right breast reveals no dominant mass or axillary adenopathy.
What is your next step?
What is the likely therapy for this patient if she is concerned about breast cosmetic appearance and preservation?
ANSWERS TO CASE 1: Breast Cancer
Summary: A 33-year-old woman has a 3-cm palpable left breast mass. The findings from an examination of the left axilla and of her right breast are normal. Her presentation is highly suspicious for left breast carcinoma.
• Next steps: Obtain tissue for diagnosis, and if a malignancy is confirmed, proceed with cancer staging, which should include bilateral mammography and breast magnetic resonance imaging (MRI) because given the age of the patient, this may provide additional valuable information regarding the size and extent of the tumor, the ipsilateral breast, axilla, and contralateral breast. Given her young age, she should also be referred to a genetic counselor for genetic testing as the result of the testing could impact the surgical plans.
• Likely therapy: If the biopsy confirms breast carcinoma, the disease is likely to be clinical stage IIa (Table 1–1), which is generally best managed by (1) first surgery and then adjuvant therapy or (2) initially systemic therapy (chemotherapy) to shrink the tumor, followed by locoregional surgical therapy (neoadjuvant). Neoadjuvant therapy is probably the best choice in this case because the patient has concerns regarding the cosmetic appearance and desires breast conservation. The result of the breast MRI is very important to help evaluate the remainder of the left breast if breast conserving therapy is contemplated. Prior to chemotherapy, the patient should be referred to a fertility specialist to consider options to preserve future fertility, as chemotherapy for breast cancers can cause cessation of ovulation.
Table 1–1 • BREAST CANCER STAGING
1. Learn the initial workup and staging process for a patient with newly diagnosed breast cancer.
2. Learn the options for locoregional and systemic therapy of breast cancer and the basis for selecting neoadjuvant therapy for certain patients.
The initial workup for this patient requires confirmation of breast cancer, including core needle biopsy and bilateral mammography. If carcinoma is confirmed, her metastatic workup should include a complete blood count (CBC), liver function tests, and chest radiography (CXR) Alternatively, staging may be accomplished with computed tomography (CT) of the chest and abdomen, or positron emissions tomography CT (PET-CT). If a biopsy confirms breast carcinoma, it is likely to be stage IIa because the lesion is between 2 and 5 cm in size (see Table 1–1), which is best managed by surgery and adjuvant therapy or by systemic therapy (neoadjuvant) prior to locoregional therapy. Mastectomy and breast conservation therapy (BCT) are both viable options because the extent of local surgery generally does not impact overall survival. Because this patient desires breast conservation therapy, neoadjuvant therapy is probably the best choice because clinical trials have showed increased success with BCT following neoadjuvant therapy. Breast MRI should be obtained to help delineate the local extent of cancer prior to considering breast conservation therapy.
APPROACH TO: Breast Carcinoma
DOMINANT BREAST MASS: A three-dimensional breast mass that persists throughout the menstrual cycle is generally considered a “dominant breast mass.”
FINE-NEEDLE ASPIRATION (FNA): A diagnostic procedure using a small-gauge needle and a syringe under vacuum for cytologic analysis, with or without image guidance. FNA can identify cancer cells but cannot differentiate invasive cancers from in situ cancers.
CORE NEEDLE BIOPSY: Large-bore (usually 10- to 14-gauge) needle biopsy that provides a histologic diagnosis. This procedure can be done with image guidance via stereotactic techniques (Figure 1–1).
Figure 1–1. Stereotactic core breast biopsy. The patient is prone on a table undergoing a biopsy with image guidance.
NEOADJUVANT CHEMOTHERAPY: Chemotherapy given prior to surgery to shrink the tumor and provide a better cosmetic result. Adjuvant therapy is chemotherapy or radiotherapy following surgery.
BREAST CONSERVATION THERAPY: Partial mastectomy with axillary staging by sentinel lymph node biopsy (SLNB) or axillary dissection. Generally, radiation therapy (to the chest wall) is added to decrease local recurrence rate.
LEVELS 1, 2, AND 3 AXILLARY NODES: Level 1 nodes are lateral to the pectoral minor muscles; level 2 nodes are deep to the pectoral minor muscles; and level 3 nodes are medial to the pectoral minor muscles.
TRIPLE RECEPTIVE-NEGATIVE BREAST CANCER: A term describing breast cancers that are estrogen, progesterone, and HER2/neu receptors negative and are being increasingly identified in premenopausal women, particularly of African American and Hispanic descents. Although these tumors are typically chemosensitive, their clinical courses are biologically aggressive resulting in early recurrences and metastases. The prognosis of patients with these tumors is poor at this time, and these tumors represent approximately 10% to 15% of all breast cancers. A number of novel treatments are currently under investigation for triple-negative tumors, and these include a number of targeted molecular therapies such as polyadenosine diphosphate ribose polymerase (PARP)-1 inhibitors and tyrosine kinase inhibitors. A recent phase II trial involving patients with metastatic triple-negative cancers demonstrated improved survival when patients received PARP-1 inhibitor + chemotherapy in comparison to those receiving chemotherapy alone.
The steps in the management of breast cancer include diagnosis, locoregional therapy, and systemic therapy. The history, clinical examination, imaging, and tissue biopsy are applied for diagnosis in most cases. Standard breast imaging includes mammography and ultrasound, and for selective patients MRI is applied. A tissue diagnosis can be obtained with FNA, core needle biopsy, or excisional biopsy. Once the tissue diagnosis confirms cancer, the extent of disease and metastasis must be defined, including evaluation of the ipsilateral and contralateral breasts. Patients with suspected stage I or II tumor could be staged with a CBC, liver function tests, and CXR. Individuals with bone pain or abdominal symptoms should be evaluated with a bone scan or an abdominal CT to rule out metastases. Stage III disease should be evaluated with a CBC, liver function tests, a CXR, a bone scan, an abdominal CT scan, and brain CT or MRI if the patient has headaches or neurologic complaints (Figure 1–2). PET is more sensitive than conventional imaging in identifying distant metastases, and in many institutions, PET + brain MRI are the modalities commonly used for disease staging. Genetic screening is strongly recommended for young patients (thirties and early forties) with new diagnoses of breast cancers. Preservation of fertility should be discussed with all premenopausal patients, as cancer treatment may lead to the loss of fertility.
Figure 1–2. The evaluation of a palpable breast mass. FNA, fine-needle aspiration; MRI, magnetic resonance imaging.
The surgical options are individualized. If the patient desires breast conservation therapy, feasibility is based on the likely cosmetic outcome, the ability to obtain negative margins safely without a total mastectomy, and the patient’s compliance with postoperative radiation therapy and follow-up breast cancer surveillance. The treatment of large lesions requiring partial mastectomy may cause significant cosmetic distortion; in such cases, patients commonly undergo neoadjuvant chemotherapy prior to surgery to shrink the tumor to obtain better cosmetic results. Alternatively, with a more favorable tumor/breast size ratio, it is often possible to perform a partial mastectomy and obtain a good cosmetic result without the use of neoadjuvant chemotherapy.
1. The first step is obtaining a tissue diagnosis and staging the breast cancer.
2. Locoregional therapy: BCT and mastectomy offer equivalent survival benefits with proper patient selection and follow-up. In addition to resection of the primary tumor, assessment of the regional lymph node basin is important for local control, accurate staging, and determination of the appropriate adjuvant therapy (such as chemotherapy and/or radiation therapy) to be undertaken. Options for nodal staging include levels 1 and 2 axillary lymph node dissection (ALND) versus sentinel lymph node biopsy (SLNB). The rationale for sentinel node sampling is to identify tumor involvement in the primary lymphatic drainage area and perform biopsy on only these nodes. The sentinel lymph nodes are localized following radiotracers and blue dye injection at the site of the primary tumor. A small incision is then made in the axilla over the areas of increased radioactivity, followed by the removal of lymph nodes with high radioactive counts and/or stained with blue dye. SLNB has been shown to provide satisfactory staging of the axilla and produce less morbidity in comparison to ALND. Traditionally, when the SLN is positive for metastasis, a complete dissection of the levels 1 and 2 axilla is performed to reduce axillary disease recurrences. The results of a randomized clinical trial published recently have suggested that not all women with axillary disease benefit from ALND. This trial was the ACOSOG Z0011 trial, which randomized patients with T1 or T2 tumors and clinically negative axilla to SLNB alone versus SLNB followed by ALND for those with positive SLNB. Their findings suggest that women with T1 and T2 invasive breast cancer do not derive clinical benefits from ALND even when the SLNB revealed the presence of cancer, because the women with positive SLNB randomized to randomized to ALND did not enjoy lower rates of axillary and systemic recurrences. The investigators from the study speculated the low incidence of axillary recurrence in patients with positive SLNB and no ALND was perhaps due to the benefits of systemic therapy and whole-breast radiation therapy that the majority of patients received.
3. Systemic therapy: Systemic therapy is given to patients who are at risk for or who have known metastatic diseases (stages III and IV). The options for treatment include surgery followed by chemotherapy or preoperative (neoadjuvant) chemotherapy followed by surgery. Patients with stage II breast cancer have a 33% to 44% risk of recurrence of the disease at 20 years with locoregional control only. For this reason, the majority of patients with stage II disease or greater are offered systemic chemotherapy in addition to locoregional control, with radiation therapy for breast-conserving surgery. Chemotherapy practice has undergone many changes over the past few years. The most common chemotherapy regimens currently used in the United States include 5-fluorouracil/doxorubicin (Adriamycin)/cyclophosphamide (FAC) and Adriamycin/cyclophosphamide (AC). Recent data suggest that the addition of docetaxel (Taxotere) to AC produces additional survival benefits when compared to FAC. Furthermore, clinical evidence demonstrates that the addition of a HER2/neu–receptor antagonist (trastuzumab) may produce additional survival benefits in patients with tumors that overexpress HER2/neu. Another aspect of chemotherapy that shows some promise is “dose-dense” therapy in which the intervals between the cycles of AC are reduced from 3 to 4 weeks to 1 to 2 weeks; clinical trials involving dose-dense therapy have produced survival benefits from cancer-related death, but this approach is associated with an increase in chemotherapy-related complications and toxicities. Generally, antiestrogen therapy is given for 5 years to patients with estrogen and/or progesterone receptor–positive tumors. Antiestrogen therapy can be given alone or after the completion of adjuvant chemotherapy. Based on the demonstration of survival advantages and fewer side effects associated with aromatase inhibitors (AIs) in postmenopausal women with ER-positive tumors, AIs have become the hormonal therapy of choice in these patients.
The implied advantages of neoadjuvant chemotherapy include in vivo determination of tumor sensitivity to therapy and improved tumor response. Despite these theoretical benefits, randomized controlled clinical trial evidence has not demonstrated a survival difference between patients treated with neoadjuvant versus adjuvant therapy. The proven advantage of neoadjuvant therapy includesimprovements in breast conservation rate and therefore likely improved cosmetic results.
1.1 A 38-year-old woman is noted on routine physical examination to have a painless 1-cm right breast mass. There is no skin dimpling or adenopathy. An FNA is performed revealing malignant cells. Which of the following is the best next step?
A. Total mastectomy
B. Partial mastectomy and radiation therapy
C. PET scan and MRI of brain
D. Core needle biopsy of mass
E. Modified radical mastectomy
1.2 A 54-year-old woman is noted to have a 1.5-cm breast mass, which on stereotactic core needle biopsy is diagnosed as invasive carcinoma. The surgeon is planning on a local tumor resection and sentinel lymph node assessment. Which of the following most accurately describes a sentinel lymph node?
A. A lymph node containing cancer metastases
B. The lymph node that is most likely to become infected postoperatively
C. The first lymph node in the lymph node basin draining a tumor
D. The only lymph node that contains metastasis
E. The surgical margins of an axillary dissection
1.3 A 60-year-old woman undergoes breast-conserving surgery (a lumpectomy) for a 0.3-cm tumor. The axillary lymph nodes are negative. Which of the following is the next step in therapy?
A. No further therapy and observation
B. Combined chemotherapy such as the AC regimen
C. A radical mastectomy
D. Axillary radiation
E. Radiation therapy to the affected breast
1.4 A 62-year-old woman complains of painful enlargement of her right breast. She has no family history of breast cancer. The right breast reveals warmth, redness, and right axilla nontender adenopathy. Which of the following is the best next step?
A. Oral antibiotic therapy
B. IV antibiotic therapy
E. PET scan
1.5 Which of the following is considered appropriate treatment option for a 53-year-old woman who develops two liver metastases two years following left modified radical mastectomy, chest wall radiation, systemic chemotherapy (A+C), and tamoxifen therapy for her T2N2, estrogen receptor positive, and HER2/neu negative invasive ductal carcinoma?
A. Aromatase inhibitor
C. Radiation therapy to the liver
D. Liver resection
E. Increase tamoxifen dose
1.1 D. Even though FNA showed cancer cells, this diagnostic modality involves cytology (loose cells) and does not allow for the differentiation of invasive versus in situ breast cancer. A core needle biopsy should be performed to determine the histology of the tumor and assess receptor status and tumor biology of the cancer. PET scan + brain MRI is the systemic staging option that may be applied for a patient with invasive cancer but is not needed if the tumor turns out to be in situ only. Mastectomy and segmental mastectomy are treatment options that should be withheld until the nature and stage of the tumor is fully determined. A modified radical mastectomy is not indicated at this time given that the diagnosis of invasive breast cancer has not yet been established, and axillary staging with axillary dissection can produce greater morbidity than SLNB; therefore, ALND is rarely applied as the initial step in axillary staging.
1.2 C. The sentinel node(s) is/are the first lymph node(s) in the lymph node basin draining a tumor. The advantages are that the procedure determines whether axillary lymph nodes contain metastasis without the extensive surgery of complete lymph node dissection.
1.3 E. Radiation therapy is indicated for a patient with stage I disease treated by BCT. The addition of radiation therapy reduces the local recurrence rate from 30% to 9%, and it is an integral part of the treatment program. Chemotherapy may or may not be indicated in a postmenopausal patient with early breast cancer. Radical mastectomy is rarely indicated for breast cancer treatment. Axillary radiation therapy is not indicated in this patient because this treatment is generally indicated only in patients with increased risk of axillary disease recurrence, such as patients with four or more axillary lymph nodes involved with cancer.
1.4 D. While it is possible for a postmenopausal or nonlactating woman with red and/or tender breasts to have developed mastitis or a breast abscess, her age and the presence of nontender axillary lymphadenopathy are highly suspicious for cancer; therefore, this patient should be assumed to have breast cancer until it is proven otherwise. A core needle biopsy or fine-needle biopsy of the tumor + punch biopsy of the involved inflamed and edematous skin is indicated. Inflammatory breast cancer is characterized by edema, redness, and tenderness caused by tumor occlusion of the dermal lymphatic channels. A PET scan would not be helpful to differentiate between infection and malignancy because both processes are associated with increase in glucose uptake and “positive” findings.
1.5 A. Aromatase inhibitor is an appropriate treatment option for this patient with ER-receptor positive tumor who develops systemic disease relapse. Trastuzumab provides only survival advantages for patients whose cancers overexpress HER2/neu. Radiation therapy to the liver is not an option because the liver is highly susceptible to radiation injury. Liver resection is not an option at this time, because the probability of other microscopic metastases in this scenario is high. However, if the patient’s liver metastases remain stable following treatment with aromatase inhibitor, she could eventually be considered for liver resection of her metastases. Another possible treatment option for this patient that is not listed is the application of additional systemic chemotherapy with Taxotere. Response to tamoxifen does not appear to be dose dependent; therefore increasing the dose of tamoxifen has not been shown to improve response
Tamoxifen therapy is associated with the development of uterine cancer.
Aromatase inhibitors are used for postmenopausal women who have ER-positive tumors.
The initial workup for a dominant breast mass generally involves obtaining tissue to characterize the breast mass and mammography to assess for other occult abnormalities.
A sentinel node biopsy can eliminate the need for axillary node dissection in selected patients.
Patients with triple negative tumors (ER negative, PR negative, and HER2/neu negative) have a poor prognosis.
Surgery and radiation therapy are locoregional treatment modalities, and chemotherapy and antiestrogen therapies are systemic treatment strategies.
Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases. The American College of Surgeon Oncology Group Z0011 Randomized Trial. Ann Surg. 2010;252:426-433.
Hunt KK, Newman LA, Copeland EM, Bland KI. The breast. In: Brunicardi FC, Andersen DK, Billiar TR, et al, eds. Schwartz’s Principles of Surgery. 9th ed. New York, NY: McGraw-Hill; 2010:423-474.
Kelley CM, Hortobagyi GN. Adjuvant chemotherapy in early-stage breast cancer: what, when, and for whom? Surg Oncol Clin N Am. 2010;19:649-668.
O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205-214.
Sledge GW Jr, Jotwani AC, Mina L. Targeted therapies in early-stage breast cancer: achievements and promises. Surg Oncol Clin N Am. 2010;19:669-679.
Yamamoto Y, Iwase H. Clinicopathological features and treatment strategy for triple-negative breast cancer. Int J Clin Oncol. 2010: DOI 10.1007/s10147-010-0106-1.