62 PRIMARY THERAPY FOR BREAST CANCER
Benjamin O. Anderson M.D.

1. How is breast cancer diagnosed?

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A diagnosis requires tissue confirmation by needle sampling or surgical biopsy. Excisional biopsy is the gold standard: the preferred initial diagnostic method has become core-needle biopsy or fine-needle aspiration (FNA). Needle sampling (1) allows complete operative planning, including decisions about lumpectomy margins or the use of sentinel node mapping and (2) does not distort the breast shape or architecture for future clinical breast examination (CBE) and breast imaging.

2. What are the limitations of needle sampling?

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Both FNA and core-needle biopsy can have false-negative results caused by sampling error. If the needle sampling diagnosis is negative for cancer and these findings correlate with the clinical presentation and breast imaging findings (mammogram and ultrasound), all of which suggest a common benign breast process (concordance), then 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), then additional tissue sampling, such as by excisional biopsy, needs to be performed.
3. How do FNA and core-needle biopsy differ? Show answer
Whereas core-needle biopsy obtains histologic specimens, similar to miniature surgical biopsy, FNA obtains cytologic specimens, similar to a Pap smear. As a result, core-needle biopsy can distinguish invasive from noninvasive (in situ) cancers, but FNA cannot (also see question 9). Cytologic interpretation requires special training and expertise. A pathologist who is comfortable reading standard surgical breast slides will also be comfortable reading breast core-needle slides, but may not be comfortable reading breast FNA.

4. Why should the breast be imaged before performing a surgical breast biopsy?

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Even with good imaging, surgeons can be surprised by histologic findings that reveal more disease in the breast than anticipated. Preoperative imaging helps surgeons optimize surgical outcomes by avoiding these surprises.
The mammogram, the road map for breast surgeons, illustrates the distribution of fatty and dense tissues within the breast. Mammography can simultaneously identify additional lesions in the same or opposite breast. Breast ultrasound is good for visualizing a specific lesion or mass within the breast. New tests such as breast MRI are currently being evaluated for their ability to assess extent of disease beyond what is seen on standard imaging once cancer is already diagnosed.

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

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Almost certainly not, if the delay is only for days or weeks. In general, breast cancers evolve slowly. Treatment should be initiated within 3-4 weeks of initial diagnosis. Delays of longer than 3-6 months should be avoided. There is more urgency with pregnancy-associated breast cancer, where tumor growth can be more rapid. It is not appropriate to delay the treatment of a breast cancer until the end of pregnancy, particularly when some chemotherapeutic agents (e.g., doxorubicin [Adriamycin]) can be safely given during pregnancy.

6. How is breast cancer staged?

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See Table 62-1.
Table 62-1. STAGING OF BREAST CANCER

7. Why is staging of breast cancer important?

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The stages correlate with likelihood of relapse and fatality. The TNM (tumor, node, 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 already have metastasized to distant sites.

8. What is the overall survival rate after definitive treatment?

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* Stage 0 (DCIS): Nearly 100% 10-year overall survival rate
* Stage I: 90% 10-year overall survival rate
* Stage II: 75% 10-year overall survival rate
* Stage III: 40% 10-year overall survival rate

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]), hormonal therapy (e.g., tamoxifen, aromatase inhibitors), and biologic therapy (e.g., herceptin) have progressively improved disease-free and overall survival in breast cancer patients, even those with advanced disease.

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

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Noninvasive (in situ) cancers are malignant cells that remain confined to the duct or lobule in which they originate. In situ cancers have minimal chance of spreading to nodes or distant sites. Invasive cancers have traversed the basement membrane of their originating duct or lobule and have metastatic potential. In situ cancers do not warrant complete lymph node dissection as part of definitive surgery. Sentinel node mapping is sometimes used in conjunction with surgical treatment of DCIS, particularly if the patient is going to undergo mastectomy or if invasive cancer is also suspected in the breast, but this has not yet been definitively proven.

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

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Breast cancer can spread to the bones, lung, liver, 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. Liver metastases can be identified using liver function tests (LFTs), which, unfortunately, are neither specific nor sensitive. Twenty-five percent of breast cancer patients with documented liver metastases have normal LFT results. Liver imaging tests (abdominal ultrasound or CT) are more expensive but are more reliable. Brain metastases are imaged by head CT or magnetic resonance imaging (MRI) scanning.

11. Which tests should be obtained before surgery to screen for metastases?

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All patients with symptoms suggesting metastatic disease (bone pain, pulmonary symptoms, jaundice, seizures) should be fully evaluated after invasive breast cancer has been diagnosed.
A standard minimal preoperative workup for invasive disease consists of a chest radiograph and LFTs. In reality, the utility of these tests among early-stage cancers is quite low. Routine chest radiography identifies unsuspected lung metastases in < 1% of patients. Chest radiography often is justified for other reasons and is useful as a baseline test for future comparison.

12. What are the alternatives for primary surgical treatment of invasive breast cancer?

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1. Modified radical mastectomy: The combined removal of the breast and axillary lymph nodes has survival benefit equivalent to radical mastectomy, which additionally removes the pectoralis muscles. True radical mastectomy is rarely performed today. The pectoralis minor muscle may be removed, with minimal morbidity, in a modified radical mastectomy to facilitate dissection of the highest (level III) lymph nodes.
2. Partial mastectomy (lumpectomy or quadrantectomy): Breast conservation therapy requires the removal of the breast tumor with a margin of normal breast tissue (negative margins), axillary dissection, and postoperative adjuvant breast irradiation. Trials with 20-year follow-up have shown equivalent survival for lumpectomy and radiation, total mastectomy, and radical mastectomy. Mastectomy is preferred when negative margins cannot be achieved.
3. Primary irradiation to the breast: This is largely investigational and cannot currently be considered a standard of care.

13. What is the National Surgical Adjuvant Breast and Bowel Program (NSABP)?

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The NSABP is a U.S.-based trialist group that performed many of the crucial randomized trials that have shaped our modern approach to breast cancer therapy. The NSABP proved that breast cancer is largely a systemic problem at the time of diagnosis and that smaller operations can be equivalent to larger ones for curative potential. Most recently, the NSABP has reported that tamoxifen can decrease the chances of high-risk women’s developing breast cancer.

14. What is the significance of the NSABP B-06 trial?

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NSABP B-06 is a multicenter study that randomized nearly 2000 women with stage I and II tumors (<4 cm) to three treatments: segmental mastectomy (SM; aka, lumpectomy) alone, SM with radiation, and total mastectomy (TM). All patients underwent axillary dissection, and patients with positive nodes received adjuvant chemotherapy. There was no difference in overall survival rates between the groups, but radiation therapy decreased local recurrence in the lumpectomized breast. In patients who underwent SM (with or without radiation), there was no difference in disease-free survival or overall survival rates, indicating that breast conservation therapy is effective for achieving both local and distant disease control.

KEY POINTS: DIAGNOSIS AND PRIMARY THERAPY FOR BREAST CANCER

1. The excisional biopsy is the gold standard for the diagnosis of breast cancer.
2. The preferred initial diagnostic method has become core-needle biopsy or fine-needle aspiration.
3. The surgical alternatives for treatment of primary invasive breast cancer are modified radical mastectomy, partial mastectomy, and primary irradiation to the breast.
4. NSABP B-06 trial found no difference in overall survival in women with stage I and II breast cancer who underwent either segmental mastectomy, segmental mastectomy with radiation, and total mastectomy, but radiation decreased local recurrence in the lumpectomized breast.

15. What is the difference among quadrantectomy, lumpectomy, and partial mastectomy?

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There really is no difference because they all refer to removing part of the breast, just in varying amounts. The original quadrantectomy promoted by the Italians in the 1980s included excision of an entire breast quadrant, along with the overlying skin. Standard lumpectomies remove less tissue and do not involve skin removal, but they still demand negative surgical margins for both invasive cancer and DCIS.

16. Are some patients poor candidates for breast conservation therapy?

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Contraindications (relative or absolute) to breast conservation include (1) cancers that cannot be excised with negative margins without mastectomy, (2) cancers that are too large relative to the breast to obtain acceptable cosmetic results, (3) multicentric cancers, and (4) patients who do not desire or who have a specific contraindication to adjuvant radiation therapy (e.g., during pregnancy).

17. What is oncoplastic surgery?

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This is a collection of procedures that use combined oncologic and reconstructive principles in performing a partial mastectomy. Large, full-thickness segments of breast are excised, often together with some overlying skin. Using mastopexy techniques, the gland is remodeled on the chest wall in order to preserve the breast’s natural shape and appearance without creating an unsightly tissue divot under the skin.

18. After mastectomy, which patients may undergo immediate breast reconstruction (i.e., during the same operation)?

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Patient selection for immediate reconstruction is controversial. Most agree that patients with noninvasive (in situ) or early invasive (stage I and selected stage II) breast cancers may be offered immediate reconstruction using a myocutaneous flap, a breast implant, or a combination of the two. It is disadvantageous to perform immediate reconstruction in patients with locally advanced (stage III) breast cancers because the patients may require postmastectomy chest wall irradiation. Radiation adversely affects the cosmetic outcome in reconstructed tissue flaps and promotes capsular contracture around implants.

19. When is chest wall radiation therapy indicated after mastectomy?

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In general, mastectomy patients do not require radiation therapy. Exceptions are those with large (>5 cm) primary cancers, positive mastectomy margins, or more than four positive axillary nodes, all of which are associated with heightened locoregional recurrence rates. The possible benefit of radiation with one to three positive axillary nodes is currently being studied.

20. What is sentinel lymph node mapping for breast cancer?

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Removing normal lymph nodes in a complete axillary lymph node dissection provides important staging information, but with some morbidity, the most notable of which is lymphedema of the arm. Alternatively, with sentinel lymph node mapping, a radioactive tracer (technetium labeled sulfur colloid), a blue dye (lymphazurin), or both are injected into the breast nodule to find the first upstream node(s) to which a primary breast cancer would spread. If the sentinel lymph nodes are negative for cancer, it is not necessary to complete the node dissection.

21. Are there risks of axillary staging by sentinel lymph node mapping?

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Sentinel node mapping appears most appropriate for smaller breast cancers with clinically normal axillae. The technique may be less reliable with large (T3) cancers and nodes extensively replaced with cancer. Thus, the primary risk of sentinel node mapping is that it may understage a patient by suggesting that the cancer is node negative when, in fact, nodal metastases are present in other “nonsentinel” lymph nodes (i.e., a false-negative result). As a result, the patient may be treated with less aggressive chemotherapy than is appropriate to minimize cancer mortality.

22. Which tests should be obtained after surgery to screen for metastases or as baseline studies for future comparison?

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The utility of metastatic screening tests correlates with the locoregional tumor and nodal (TN) staging determined at surgery. Patients with locally advanced (stage III and some stage II) cancers are at high risk for developing cancer recurrence with metastases, making additional diagnostic studies valuable. Bone scan and liver imaging (CT or ultrasound) are helpful baseline studies that occasionally reveal previously unappreciated metastatic disease. Some clinicians use circulating tumor markers such as CEA CA-27, 29 to follow treatment results and monitor for evidence of cancer recurrence, although the value of these studies is debatable.
Conversely, baseline studies are best avoided in asymptomatic patients with early cancers because the chance of a false-positive test is vastly higher than the chances of finding clinically occult distant metastases. For example, with stage I breast cancer, the likelihood of a false-positive result on bone scans vastly exceeds the likelihood of a true-positive result. Similarly, brain imaging (CT or MRI) generally should be reserved for patients with neurologic symptoms because of low yield in asymptomatic patients.

23. What is “neoadjuvant” therapy for breast cancer?

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Locally advanced but operable (stage IIIA and some stage II) cancers have a high likelihood of recurrence after surgery. Neoadjuvant therapy (before surgery) is used to decrease the local tumor burden and to begin treatment of micrometastatic disease at the earliest possible time. It is not yet known whether the timing of chemotherapy relative to surgery influences survival time from diagnosis. Neoadjuvant chemotherapy may convert some cancers that otherwise might require mastectomy into potential candidates for breast conservation surgery.

24. What is “inoperable” breast cancer?

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Inoperable breast cancer has advanced beyond the boundaries of surgical resection. The spread may be regional (internal mammary lymph nodes, stage IIIB) or distant (distant metastases, stage IV). Supraclavicular lymph node metastases, which are beyond the margins of surgical resection, confer the same unfortunate prognosis as metastasis to distant solid organs and currently are staged as such. Primary therapy for advanced cancer is systemic treatment (chemotherapy or hormonal therapy) rather than surgery. Surgery combined with radiation therapy becomes an adjuvant therapy for local control of disease after a good response to systemic treatment.

25. How is DCIS treated?

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As the earliest form of breast cancer requiring treatment, DCIS has the widest range of treatment choices. Because it lacks metastatic potential, DCIS does not require systemic drug treatment. Also called intraductal carcinoma, DCIS can be safely treated by breast conservation therapy (lumpectomy plus adjuvant radiation), provided that the disease is excised with negative margins. If negative margins cannot be achieved, then mastectomy is recommended. Axillary dissection for staging is not indicated. Tamoxifen may play a role in breast cancer prevention, and it lowered local recurrence after lumpectomy and radiation in the NSABP B-24 trial.

26. Can some cases of DCIS be treated by lumpectomy without radiotherapy?

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Using carefully collected retrospective data, Silverstein et al. developed a prognostic index (scoring system) for DCIS based on histologic grade, tumor size, and margin width. Their data suggest that small (< 1 cm), non-high-grade DCIS lesions excised with wide surgical margins do not require radiation therapy in addition to lumpectomy. However, forgoing radiation treatment after lumpectomy for DCIS remains controversial. Recent reports suggest that late local recurrence rates (≤ 25 years) for non-high-grade DCIS may exceed 25%.

27. How does DCIS management differ from that for lobular carcinoma in situ (LCIS)?

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DCIS is considered a preinvasive malignancy. It is treated surgically with lumpectomy or mastectomy, with or without radiation therapy, similar to how invasive breast cancer is treated. By contrast, LCIS is viewed as a risk factor for the development of subsequent breast cancer and is generally not thought to be “cancer” per se. LCIS does not require surgery.

28. Why are patients with LCIS not treated surgically?

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LCIS does not invariably degenerate into invasive cancer, but women with proven LCIS have a 25% chance of developing breast cancer during their lifetimes. Unfortunately, the cancer may be ductal or lobular and may develop with equal likelihood in either breast. LCIS is a marker for high breast cancer risk, warranting careful surveillance with serial mammography and physical examination. Because risk is the same in both breasts, bilateral mastectomy is the only logical surgical procedure for this condition, and aggressive therapy simply is not warranted.

29. Can drugs be used to prevent breast cancer among high-risk women?

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In the NSABP P-01 Tamoxifen Prevention Trial, women at heightened risk for the development of breast cancer (> 1.66% 5-year risk) developed fewer breast cancers when given tamoxifen rather than placebo. For women with LCIS, the 5-year breast cancer incidence was 6.8% in the placebo group and 2.5% in the tamoxifen group, representing a 56% reduction in breast cancers. However, the number of breast cancers that were prevented rivaled the number of tamoxifen-associated complications, including endometrial cancers and thrombotic events. No survival benefit to tamoxifen prophylaxis has yet been observed. At this time, women with LCIS should be offered tamoxifen as an option for treatment and cancer prevention, although they may reasonably decline when presented with the complete data.

References
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BIBLIOGRAPHY
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