Primary Therapy for Breast Cancer

1

How is breast cancer diagnosed?

A breast cancer diagnosis requires tissue confirmation by needle sampling or less commonly by surgical biopsy. Historically, excisional biopsy was the gold standard, but needle sampling has become the preferred initial diagnostic method most often using core needle biopsy. Needle sampling is desirable because it does not create skin incisions that adversely affect surgical planning in the event a therapeutic surgical procedure is needed. Needle sampling is also desirable for long-term follow-up in the case of benign biopsies because it does not distort the breast shape or architecture for future clinical breast examination (CBE) and breast imaging. While surgical excision can be used for diagnosis, it is often undesirable as an initial step for cancers because the operation generally will not be adequate as a therapeutic procedure and also requires the creation of skin incisions that may be undesirable for subsequent lumpectomy or mastectomy planning.

2

What are the limitations of needle sampling?

The two options for needle sampling are fine-needle aspiration (FNA) and core needle biopsy. FNA may be used when core sampling is not feasible, but FNA provides more limited information about the sampled lesion. Both FNA and core needle biopsy can have false-negative results caused by sampling error. As a result, comprehensive diagnostic evaluation requires triple test evaluation where needle sampling results are compared with clinical evaluation (history and physical exam) and breast imaging (mammogram and ultrasound [US]) to determine if further tissue sampling is warranted or if the patient may be followed clinically. If the needle sampling diagnosis is negative for cancer and these findings correlate with the clinical presentation and breast imaging findings (mammogram and US), all of which suggest a benign breast process (concordance), the patient may have clinical follow-up examination without further intervention. However, if the needle sampling results do not match the findings from clinical examination or breast imaging (discordance), additional tissue sampling with a surgical excisional biopsy should be considered.

3

How do fine needle aspiration and core needle biopsy differ?

FNA cytology is technically simple to perform, can be read immediately, and is cheap. By comparison, core needle biopsy, like surgical biopsy, requires that the specimen sit in fixative overnight. However, core needle sampling can allow complete operative planning, including decisions about lumpectomy versus mastectomy and/or the use of sentinel node mapping or complete axillary node dissection for staging. Because FNA is cytologic rather than histologic sampling, it cannot distinguish between invasive and in situ cancers. FNA cytology requires an expert cytologist for correct interpretation. Centers with specialized cytology expertise can set up effective systems where women are promptly and effectively evaluated, often with same-day diagnosis at significantly lower cost. However, the perceived complexity of FNA-based diagnostic systems have led most United States-based centers to base their diagnostic workup on core needle biopsy.

By contrast to FNA, core needle biopsy (using standard 14-gauge or large-bore 8-gauge vacuum-assisted sampling) obtains true histology specimens that functionally resemble miniature surgical biopsies. Core needle samples do not distort the breast tissue nor do they leave large scars after healing, making them clearly preferable to surgical biopsy. Core biopsy can distinguish invasive from noninvasive cancer, ductal from lobular histology, and high-grade from low-grade disease. Special sections of core needle biopsy specimens can be prepared for immunohistochemistry staining to determine estrogen receptor (ER), progesterone receptor (PR), and Her-2/neu oncogene overexpression status. A pathologist skilled in reading standard surgical breast slides should also be comfortable reading breast core needle slides but may not be comfortable interpreting a breast FNA. Because of its versatility and the relative paucity of breast cytology expertise, core needle biopsy has become the most commonly accepted diagnostic standard for tissue sampling of the breast in the United States.

4

Why should the breast be imaged before performing a breast biopsy?

Breast cancer generally begins as clinically occult disease that evolves to become palpable as the cancer grows and induces fibrosis in the breast. Even experienced surgeons can be surprised to find that seemingly small palpable cancers can be much more extensive in the breast than anticipated based on CBE alone. Preoperative imaging helps surgeons optimize surgical outcomes by avoiding these surprises and correctly assessing the extent of disease in the breast and/or axilla prior to embarking on surgical treatment. In some settings, breast imaging can allow the clinician to forego tissue sampling (e.g., simple cysts seen on breast US).

Specific breast imaging tools include mammography, US, and magnetic resonance imaging (MRI):

• The mammogram is the surgeon’s road map, illustrating the distribution of fatty and dense tissues within the breast and simultaneously identifying additional lesions in the same or opposite breast that might warrant surgical attention. Screening mammograms are used in asymptomatic patients as part of a population-based screening program intended to increase the fraction of cancers diagnosed at earlier stage. Diagnostic mammogram is used when there is a clinical complaint or when the screening images have demonstrated a finding that needs additional investigation.

• Diagnostic breast US is a powerful tool for visualizing mammographically detected localized breast masses or palpable findings and can be used to guide needle sampling. Screening whole-breast US has been evaluated and can increase the number of screen-detected cancers but is generally not used routinely because of the large number of false-positive US findings warranting US-guided biopsy and/or interval follow-up.

• Breast MRI is used for breast cancer screening among women at significantly increased breast cancer risk on the basis of strong family history, especially when they have dense breasts on mammographic imaging. Many cancer centers use MRI with newly diagnosed breast cancers to assess extent of disease beyond what is seen on standard imaging. Surgeons can have a “love-hate” relationship with MRI because on the one hand it can give excellent delineation of the extent of existing cancers, but on the other hand it has a high false-positive rate of 20%–30%, requiring additional evaluation or even MRI-guided biopsy. MRI sometimes finds very small foci of breast cancer at some distance from the known primary, a disease that most likely would respond to radiation therapy and/or systemic therapy, but once found needs to be removed.

5

Does a delay between biopsy and definitive treatment adversely affect cure?

Generally no, as long as the delay is only for days or weeks. Breast cancers typically evolve slowly, so treatment should be initiated within 3–4 weeks of initial diagnosis, if possible. Delays of longer than 3–6 months should be avoided. There is more urgency with pregnancy-associated breast cancer, in which tumor growth can be much more rapid. It is not appropriate to postpone the treatment of a breast cancer until the end of pregnancy, unless the pregnancy is almost to term. The standard of care for breast cancer diagnosed during the second or third trimesters is to start neoadjuvant chemotherapy. Some chemotherapeutic agents such as doxorubicin (Adriamycin) can be safely given during the second and third trimesters of pregnancy because it does not cross the placental barrier.

6

How is breast cancer staged?

See Table 66.1 .

7

Why is staging of breast cancer important?

Breast cancer stage correlates with likelihood of relapse and mortality. Tumor, node, and metastasis staging summarizes data about tumor size, axillary node metastases, and distant metastases. Stage 0 cancers are noninvasive cancers (e.g., ductal carcinoma in situ [DCIS]); stage I breast cancers are small node-negative invasive cancers; stage II cancers are intermediate-sized cancers with or without axillary nodal metastases; stage III cancers are locally advanced cancers, usually with axillary nodal metastases; and stage IV cancers are those that have already metastasized to distant sites.

Staging is important because it is a framework for planning adjuvant drug therapy and radiation treatment, both of which are critical to reducing breast cancer recurrence rates. Randomized trials that have proven treatment efficacy use stage as a basis for selected patient groups that are reasonably uniform. The staging framework also gives clinicians a standardized shorthand vocabulary for presenting clinical scenarios that are intuitively clear and understandable. For example, a T3N0 cancer is large but node negative, while a T1aN2 cancer is very small but has significant nodal burden.

8

What is the overall survival rate after definitive multimodality treatment with curative intent?

• Stage 0 (DCIS): Nearly 100% 10-year overall disease-specific survival rate

• Stage I: 90% 10-year overall disease-specific survival rate

• Stage II: 75% 10-year overall disease-specific survival rate

• Stage III: 40% 10-year overall disease-specific survival rate

• Stage IV: Cancer with distant metastases

A gradual incremental improvement in breast cancer survival over recent years has been attributed to earlier detection and improved systemic therapy. Cytotoxic chemotherapy (e.g., CMF, Adriamycin, paclitaxel [Taxol]) for hormone-receptor negative cancers, hormonal therapy (e.g., tamoxifen, aromatase inhibitors) for hormone-receptor positive cancers, and biologic therapy (e.g., Herceptin for Her-2/neuoncogene overexpressing cancers) have improved disease-free and overall survival in breast cancer patients, even those with advanced disease.

The management of metastatic (stage IV) breast cancer represents a fundamental therapeutic shift from that of stage 0–III disease. Instead of treating with curative intent, metastatic breast cancer receives tailored minimally morbid therapeutic regimens with the goal of stabilizing disease rather than permitting progression. The goal is to optimize quality of life, and some prolongation of life can be achieved in some circumstances. While cures can, on rare occasions, occur because of unusually favorable biologic response to treatment, stage IV breast cancer is generally assumed to be incurable and will eventually take the patient’s life.

9

What is the difference between noninvasive (in situ) and invasive breast cancers?

Noninvasive (in situ) cancers are lesions in which the malignant cells remain confined to the ductal tree or segment in which they originated. In situ cancers have minimal chance of spreading to nodes or distant sites. Invasive cancers have infiltrated through the basement membrane of their originating duct or lobule and concomitantly may have developed metastatic potential. In situ cancers have cells that are largely biologically incompetent and are unable to establish growth in distant tissues, so even if cells from these early cancers “escape” from the duct or are pushed into surrounding tissues during needle sampling, they remain unable to create metastatic disease. Thus, the primary reason for treating in situ cancer is to stop it from transforming into invasive cancer that does have the potential to spread to distant sites.

While DCIS and lobular carcinoma in situ (LCIS) are both in situ lesions, DCIS is generally treated surgically, while LCIS generally is not. DCIS has a higher risk of progression to invasive disease at the site where it is occurring in the breast, making local control of disease an appropriate intervention in most cases. LCIS, by contrast, is associated with an increased risk of subsequent invasive cancer, but that subsequent invasive disease following LCIS diagnosis is likely to be somewhere else in the breast or even in the opposite breast. For this reason, DCIS is generally considered preinvasive cancer, while LCIS is considered a breast cancer risk factor.

Complete axillary lymph node dissection (ALND) is not warranted for staging DCIS because the risk of nodal metastasis is remote. However, selective “sentinel lymphadenectomy,” in which node mapping techniques are used to find and remove the “first upstream” node or nodes, may be used in conjunction with surgical treatment of DCIS, especially when a total mastectomy is planned. Sentinel node biopsy can only be performed with the breast in place and is no longer possible following mastectomy. If a mastectomy is performed for presumed DCIS and then occult invasive cancer is found, minimally invasive axillary staging is no longer possible. Surgeons need to think ahead to avoid this situation.

10

Where does invasive breast cancer spread (other than to lymph nodes)? Which diagnostic tests are useful for identifying such metastases?

Breast cancer can spread to the bones, lung, liver, peritoneal surfaces, and brain. Bone scans are quite sensitive but less specific for bone metastases. Standard radiographs help distinguish metastases from benign inflammatory conditions. Lung metastases are identified by chest radiographs or computed tomography (CT) scan with or without PET scan. Liver metastases can be identified using liver function tests (LFTs), but these tests are neither specific nor sensitive, with 25% of breast cancer patients with documented liver metastases having normal LFT results. Liver imaging tests (abdominal CT with or without PET scan, US, or MRI) are more expensive but more reliable. Brain metastases are imaged by head CT or MRI scanning, but only in the symptomatic patient.