Radiation therapy is used for all stages of breast cancer depending on whether the patient is undergoing BCT or mastectomy.264,265,266,267,268,269,270 Adjuvant radiation for patients with DCIS and early-stage breast cancer are described above. Those women treated with mastectomy who have cancer at the surgical margins are at sufficiently high risk for local recurrence to warrant the use of adjuvant radiation therapy to the chest wall postoperatively. Women with metastatic disease involving four or more axillary lymph nodes and premenopausal women with metastatic disease involving one to three lymph nodes also are at increased risk for recurrence and are candidates for the use of chest wall and supraclavicular lymph node radiation therapy. In advanced local-regional breast cancer (stage IIIA or IIIB), women are at high risk for recurrent disease after surgical therapy, and adjuvant radiation therapy is used to reduce the risk of recurrence. Current recommendations for stages IIIA and IIIB breast cancer are: (a) adjuvant radiation therapy to the breast and supraclavicular lymph nodes after neoadjuvant chemotherapy and segmental mastectomy with or without axillary lymph node dissection, (b) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after neoadjuvant chemotherapy and mastectomy with or without axillary lymph node dissection, and (c) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after segmental mastectomy or mastectomy with axillary lymph node dissection and adjuvant chemotherapy.
The use of partial breast irradiation (APBI) for patients treated with breast-conserving surgery is also described above. APBI can be delivered via brachytherapy, external beam radiation therapy using three-dimensional conformal radiation, or intensity-modulated radiation therapy. Although initial results are promising in highly selected low-risk populations, APBI should be used in the clinical setting only as part of a prospective trial.
The Early Breast Cancer Trialists’ Collaborative Group overview analysis of adjuvant chemotherapy demonstrated reductions in the odds of recurrence and of death in women ≤70 years of age with stage I, IIA, or IIB breast cancer.118,271,272,273,274,275 For those ≥70 years of age, the lack of definitive clinical trial data regarding adjuvant chemotherapy prevented definitive recommendations. Adjuvant chemotherapy is of minimal benefit to women with negative nodes and cancers ≤0.5 cm in size and is not recommended. Women with negative nodes and cancers 0.6 to 1.0 cm are divided into those with a low risk of recurrence and those with unfavorable prognostic features that portend a higher risk of recurrence and a need for adjuvant chemotherapy. Adverse prognostic factors include blood vessel or lymph vessel invasion, high nuclear grade, high histologic grade, HER-2/neu overexpression, and negative hormone receptor status. Adjuvant chemotherapy is recommended by the NCCN guidelines for women with these unfavorable prognostic features. Table 17-14 lists the frequently used chemotherapy regimens for breast cancer.
Table 17-14Adjuvant chemotherapy regimens for breast cancer ||Download (.pdf) Table 17-14 Adjuvant chemotherapy regimens for breast cancer
For women with hormone receptor-negative cancers that are >1 cm in size, adjuvant chemotherapy is appropriate. However, women with node-negative hormone receptor–positive cancers and T1 tumors are candidates for antiestrogen therapy with or without chemotherapy. Assessment of overall risk using known prognostic factors or additional testing such as the 21-gene recurrence score assay can help to guide decision making regarding chemotherapy in patients with node-negative ER-positive breast cancer. For special-type cancers (tubular, mucinous, medullary, etc), which are usually strongly estrogen receptor positive, adjuvant antiestrogen therapy should be advised for cancers >1 cm. For women with node-positive tumors or with a special-type cancer that is >3 cm, the use of chemotherapy is appropriate: those with hormone receptor-positive tumors should receive antiestrogen therapy.
For stage IIIA breast cancer preoperative chemotherapy with an anthracycline-containing or taxane-containing regimen followed by either a modified radical mastectomy or segmental mastectomy with axillary dissection followed by adjuvant radiation therapy should be considered, especially for estrogen receptor negative disease. While the same regimen may be considered for estrogen receptor positive disease it is known that these tumors respond less well to chemotherapy with <10% pCR rate overall and <3% pCR rate for lobular cancers. Other options such as neoadjuvant endocrine therapy followed by local-regional treatment or in a minority of cases primary endocrine therapy may be considered depending on other tumor characteristics and the patient’s co-morbid conditions and preference.
Neoadjuvant (Preoperative) Chemotherapy
In the early 1970s, the National Cancer Institute in Milan, Italy, initiated two prospective randomized multimodality clinical trials for women with T3 or T4 breast cancer.276 The best results were achieved when surgery was interposed between chemotherapy courses, with 82% local-regional control and 25% having a 5-year disease-free survival. The NSABP B-18 trial evaluated the role of neoadjuvant chemotherapy in women with operable stage II and III breast cancer.188 Women entered into this study were randomly assigned to receive either surgery followed by chemotherapy or neoadjuvant chemotherapy followed by surgery. There was no difference in the 5-year disease-free survival rates for the two groups, but after neoadjuvant chemotherapy there was an increase in the number of lumpectomies performed and a decreased incidence of node positivity. It was suggested that neoadjuvant chemotherapy be considered for the initial management of breast cancers judged too large for initial lumpectomy.
Several prospective clinical trials have evaluated the neoadjuvant approach and two meta-analyses have been performed each showing that neoadjuvant vs. adjuvant chemotherapy are equivalent in terms of OS.237,277 These analyses also evaluated local-regional recurrence (LRR) and found that there was an increase in LRR rates for patients receiving neoadjuvant chemotherapy when radiation therapy was used alone without surgery after completion of chemotherapy. Mittendorf and colleagues evaluated a contemporary series of almost 3000 patients treated with breast conserving surgery and radiation therapy who received either neoadjuvant or adjuvant chemotherapy for breast cancer.278 They found that the risk of LRR was driven by biologic factors and disease stage and was not impacted by the timing of chemotherapy delivery. These data highlight the importance of the multidisciplinary management of patients with breast cancer in achieving the best outcomes.
The use of neoadjuvant chemotherapy offers the opportunity to observe the response of the intact primary tumor and any regional nodal metastases to a specific chemotherapy regimen.279 For patients whose tumors remain stable in size or even progress with the initial neoadjuvant chemotherapy regimen, a new regimen may be considered that uses another class of agents, although there is no randomized data confirming this will improve outcome.
After treatment with neoadjuvant chemotherapy, patients are assessed for clinical and pathologic response to the regimen. Patients whose tumors achieve a pathologic complete response to neoadjuvant chemotherapy have been shown to have statistically improved survival outcomes to those of patients whose tumors demonstrate only a partial response, remain stable, or progress on treatment. Patients who experience progression of disease during neoadjuvant chemotherapy have the poorest survival.280,281 This means that while patients who achieve a pCR will have a better outlook based on their response to neoadjuvant chemotherapy. Equally other patients will have a poorer outlook compared to when they started neoadjuvant therapy based on the non-response to treatment. The FDA is now proposing to use the neoadjuvant platform and pathologic response rates as a mechanism of accelerated approval for new agents although the short term endpoints (i.e., pCR) have not yet been shown to correlate with long-term outcomes (i.e., disease free survival and overall survival).
Current NCCN recommendations for treatment of operable advanced local-regional breast cancer are neoadjuvant chemotherapy with an anthracycline-containing or taxane-containing regimen or both, followed by mastectomy or lumpectomy with axillary lymph node dissection if necessary, followed by adjuvant radiation therapy. For patients with HER-2-positive breast cancer, trastuzumab can be combined with chemotherapy in the preoperative setting to increase pathologic complete response rates. For inoperable stage IIIA and for stage IIIB breast cancer, neoadjuvant chemotherapy is used to decrease the local-regional cancer burden. This may then permit subsequent modified radical or radical mastectomy, which is followed by adjuvant radiation therapy.
Nodal Evaluation in Patients Receiving Neoadjuvant Chemotherapy
The management of the axilla after neoadjuvant chemotherapy has not been specifically addressed in randomized trials. Standard practice has been to perform an axillary lymph node dissection after chemotherapy or to perform a sentinel lymph node dissection before chemotherapy for nodal staging before chemotherapy is initiated. A number of small single-institution studies, one multicenter study, and a recent meta-analysis have explored the use of SLN dissection at the completion of chemotherapy. The published results from these studies have demonstrated the feasibility of SLN dissection in breast cancer patients after neoadjuvant chemotherapy. Review of 14 studies with 818 patients showed a false negative rate of 11% with an overall accuracy of 94%.251,252,282 Although the issue has not been specifically addressed in the published trials, the presence of suspected or documented axillary metastases at initial presentation generally is considered a contraindication to SLN dissection after neoadjuvant chemotherapy, and these patients usually undergo axillary lymph node dissection after completion of chemotherapy.
Neoadjuvant Endocrine Therapy.
There is little randomized data on neoadjuvant endocrine therapy and virtually none which reports local recurrence rates. Neoadjuvant endocrine therapy has not been based on randomized controlled trials. It has most commonly been used in elderly women who were deemed poor candidates for surgery or cytotoxic chemotherapy. As clinicians have gained experience with neoadjuvant treatment strategies, it is now clear from examination of predictors of complete pathologic response that ER-positive tumors do not shrink in response to chemotherapy as readily as ER-negative tumors.283 Indeed the pCR rate in estrogen receptor negative tumors is approximately three times that of estrogen receptor positive tumors. Fisher et al examined the results of the NSABP B-14 and B-20 trials and found that, as age increased, women obtained less benefit from chemotherapy. They recommended that factors194 including tumor estrogen receptor concentration, nuclear grade, histologic grade, tumor type, and markers of proliferation should be considered in these patients before choosing between the use of chemotherapy and hormonal therapy. If in fact the tumor is estrogen receptor rich, these patients may benefit more from endocrine therapy in the neoadjuvant setting than they might if they received standard chemotherapy. Neoadjuvant endocrine therapy has been shown to shrink tumors, enabling breast-conserving surgery in women with hormone receptor-positive disease who otherwise would have to be treated with mastectomy although long-term recurrence rates have not been reported.284
With the use of neoadjuvant chemotherapy or endocrine therapy, observation of the response of the intact tumor and/or nodal metastases to a specific regimen could ultimately help to define which patients will benefit from specific therapies in the adjuvant setting. In adjuvant trials the primary endpoint is typically survival, whereas in neoadjuvant trials the endpoints have more often been clinical or pathologic response rates. However, with the reported increase in local recurrence and the link between local recurrence and survival by the Early Breast Cancer Trialists’ Collaborative Group, surgeons need to become more focused on local recurrence as a primary endpoint of neoadjuvant therapies. There are a number of clinical trials underway comparing neoadjuvant chemotherapy and endocrine therapy regimens with pretreatment and posttreatment biopsy samples obtained from the primary tumors in all of the participants. These samples are being subjected to intensive genomic and proteomic analyses that may help to define a more personalized or individualized approach to breast cancer treatment in the future.
Within the cytosol of breast cancer cells are specific proteins (receptors) that bind and transfer steroid moieties into the cell nucleus to exert specific hormonal effects.274,285,286,287,288,289 The most widely studied hormone receptors are the estrogen receptor and progesterone receptor. Hormone receptors are detectable in >90% of well-differentiated ductal and lobular invasive cancers. Although the receptor status may remain the same between the primary cancer and metastatic disease in the same patient in the vast majority of cases, there are instances where the status is changed in the metastatic focus and therefore biopsy of newly diagnosed metastatic disease should be considered for assessment of hormone receptor and HER-2 status.
After binding to estrogen receptors in the cytosol, tamoxifen blocks the uptake of estrogen by breast tissue. Clinical responses to antiestrogen are evident in >60% of women with hormone receptor-positive breast cancers but in <10% of women with hormone receptor-negative breast cancers. A meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group showed that adjuvant therapy with tamoxifen for 5 years reduced breast cancer mortality by about a third through the first 15 years of follow-up.290 This mortality benefit continues to be statistically significant in the second and third 5-year periods (i.e., years 5–9 and 10–15) when the patients are no longer receiving endocrine treatment—the so called ‘carry-over effect’. The analysis also showed a 39% reduction in the risk of cancer in the contralateral breast. The antiestrogens do have defined toxicity, including bone pain, hot flashes, nausea, vomiting, and fluid retention. Thrombotic events occur in <3% of treated women. Cataract surgery is more frequently performed in patients receiving tamoxifen. A long-term risk of tamoxifen use is endometrial cancer. Tamoxifen therapy usually is discontinued after 5 years although recent data from randomized trials suggest a survival benefit for 10 years of tamoxifen therapy over 5 years. However, somewhat surprisingly the benefit is not seen in the second five years (i.e., years 5–9) while the patients are on treatment but only from years 10–15. In high risk patients who have received 5 years of adjuvant tamoxifen extended adjuvant therapy with at least 3 years of an aromatase inhibitor has been shown to provide a significant benefit in terms of disease outcome.291
Tamoxifen therapy is also considered for women with DCIS that is found to be estrogen receptor positive on immunohistochemical studies. The goals of such therapy are to decrease the risk of an ipsilateral recurrence after breast conservation therapy for DCIS and to decrease the risk of a primary invasive breast cancer or a contralateral breast cancer event. This approach has not been universally accepted.
In postmenopausal women, aromatase inhibitors are now considered first-line therapy in the adjuvant setting or as a secondary agent after 1 to 2 years of adjuvant tamoxifen therapy. The nonsteroidal third generation aromatase inhibitors, anastrozole and letrozole, have both been shown to result in significantly fewer local and distant recurrences.292,293 While neither trial on its own has shown a significant survival advantage, an overview of all the studies of adjuvant aromatase inhibitors has reported a survival advantage to the use of aromatase inhibitors The HR is about 0.80 for 5 years of an aromatase inhibitor vs. 5 years of tamoxifen and this is irrespective of absolute risk. This has led some to suggest a switch policy—2 years of tamoxifen followed by 3 years of an aromatase inhibitor—for low risk patients where the absolute benefits may be small and the cost of an aromatase inhibitor may be significant for some individuals. As aromatase inhibitors come off patent, the cost issue should decrease and even for small benefits the additional cost of an aromatase inhibitor should become cost-effective. Whether 10 years of an aromatase inhibitor will be better than 5 years is currently the subject of a randomised trial by the NSABP (B-42). For patients who have completed 5 years of adjuvant endocrine therapy and are 6–20 years from presentation, the question of whether reintroducing endocrine therapy might decrease long term recurrence rates is being addressed by the later study which randomizes patients to 5 years of letrozole or placebo.
The aromatase inhibitors are less likely than tamoxifen to cause endometrial cancer but do lead to changes in bone mineral density that may result in osteoporosis and an increased rate of fractures in postmenopausal women. The risk of osteoporosis can be averted by treatment with bisphosphonates. Joint pains are a side effect which affects a significant number of patients.
Node-negative and node-positive breast cancer patients whose tumors express hormone receptors should be considered for endocrine therapy in the adjuvant setting. Women with hormone receptor-positive cancers achieve significant reduction in risk of recurrence and mortality due to breast cancer through the use of endocrine therapies. For women with stage IV breast cancer, a third generation non-steroidal aromatase inhibitor is the preferred initial therapy. For postmenopausal women with prior aromatase inhibitor exposure, recommended second-line endocrine therapies include the pure anti-estrogen fulvestrant (at the 500-mg dose) or tamoxifen followed by progestins, high-dose estrogen, and androgens. For postmenopausal patients who received tamoxifen as prior endocrine therapy, subsequent endocrine therapies would be an aromatase inhibitor or fulvestrant (500 mg) followed by progestins, high dose estrogens, and androgens. In premenopausal patients with stage IV breast cancer either tamoxifen or oophorectomy (medical, surgical, or radioablative) could be used alone with the other then being added in on progression. An overview of four randomized trials suggested combining oophorectomy and tamoxifen would be the initial treatment options. If a tumor progresses while a premenopausal patient is on ovarian ablation plus tamoxifen then the tamoxifen can be stopped and an aromatase inhibitor added to the ovarian ablation. Subsequent therapies if the patient’s tumor is still deemed to be potentially hormone responsive can include ovarian ablation plus fulvestrant, ovarian ablation plus exemestane, and then progestins followed by high dose estrogens. Women whose tumors respond to an endocrine therapy with either shrinkage of their breast cancer (objective response) or long-term stabilization of disease (stable disease) are together consider to represent ‘clinical benefit’ and should receive additional endocrine therapy at the time of progression since their chances of a further response remain high.294,295,296 Patients whose tumors progress de-novo on an endocrine agent have a low rate of clinical benefit (<20%) to subsequent endocrine therapy; the choice of endocrine or chemotherapy should be considered based on the disease site and extent as well as the patient’s general condition and treatment preference.294
Ablative Endocrine Therapy
In the past, oophorectomy, adrenalectomy, and/or hypophysectomy were the primary endocrine modalities used to treat metastatic breast cancer, but today they are rarely used. Oophorectomy was used in premenopausal breast cancer patients. In contrast, pharmacologic doses of exogenous estrogens were given to postmenopausal women with similar recurrences. For both groups, the response rates were nearly 30%. Adrenalectomy and hypophysectomy were effective in individuals who had previously responded to either oophorectomy or exogenous estrogen therapy, and the response to these additional procedures was nearly 30%. Aminoglutethimide blocks enzymatic conversion of cholesterol to γ-5-pregnenolone and inhibits the conversion of androstenedione to estrogen in peripheral tissues. Dose-dependent and transient side effects include ataxia, dizziness, and lethargy. After treatment with this agent (medical adrenalectomy), adrenal suppression necessitates glucocorticoid therapy. Neither permanent adrenal insufficiency nor acute crises have been observed. Because the adrenal glands are the major site for production of endogenous estrogens after menopause, treatment with aminoglutethimide has been compared prospectively with surgical adrenalectomy and hypophysectomy in postmenopausal women and is equally efficacious.
The determination of tumor HER-2/neu expression or gene amplification for all newly diagnosed patients with breast cancer is now recommended.297,298,299,300 It is used to assist in the selection of adjuvant chemotherapy in both node-negative and node-positive patients. Patients with HER-2-positive disease appear to have better outcomes with anthracycline-based adjuvant chemotherapy regimens. Patients with HER-2-positive tumors benefit if trastuzumab is added to paclitaxel chemotherapy. Cardiotoxicity may develop if trastuzumab is delivered concurrently with anthracycline-based chemotherapy.
Trastuzumab was initially approved for the treatment of HER-2/neu–positive breast cancer in patients with metastatic disease. Once efficacy was demonstrated for patients with metastatic disease, the NSABP and the North Central Cancer Treatment Group conducted phase III trials evaluating the impact of adjuvant trastuzumab therapy in patients with early-stage breast cancer. After approval from the FDA, these groups amended their adjuvant trastuzumab trials (B-31 and N9831, respectively), to provide for a joint efficacy analysis. The first joint interim efficacy analysis demonstrated an improvement in 3-year disease-free survival from 75% in the control arm to 87% in the trastuzumab arm (hazard ratio = 0.48, P<.0001). There was an accompanying 33% reduction in mortality in the patients who received trastuzumab (hazard ratio = 0.67, P = 0.015). The magnitude of reduction in hazard for disease-free survival events crossed prespecified early reporting boundaries, so the data-monitoring committees for both groups recommended that randomized accrual to the trials be ended, and the results were subsequently published.167
Buzdar and colleagues reported the results of a randomized neoadjuvant trial of trastuzumab in combination with sequential paclitaxel followed by FEC-75 (5-fluorouracil, epirubicin, cyclophosphamide) vs. the same chemotherapy regimen without trastuzumab in 42 women with early-stage operable breast cancer. The pathologic complete response rates in this trial increased from 25 to 66.7% when chemotherapy was given concurrently with trastuzumab. None of the patients receiving the concurrent trastuzumab and FEC regimen developed symptoms of congestive heart failure. However, given the small sample size in this report, the 95% confidence interval for developing heart failure was 0% to 14.8%.301 A subsequent report which included additional patients treated with concurrent chemotherapy and trastuzumab further confirmed the high pathologic complete response rates and continued to show that cardiac function was preserved.302 This regimen was tested in a phase III multicenter trial (ACOSOG Z1041) which recently completed accrual.
Several new agents have been approved for the treatment of women with metastatic HER-2-positive breast cancers. Lapatinib is a dual tyrosine kinase inhibitor that targets both HER-2 and EGFR. It was approved for use with capecitabine in patients with HER-2-positive metastatic disease. Ado-trastuzumab (previously known as TDM1) was approved for patients who have previously received trastuzumab and a taxane either separately or in combination. Ado-trastuzumab binds to the HER-2 receptor and releases a cytotoxic agent into the cell that leads to apoptosis. The FDA has also approved pertuzumab, which also targets the HER-2 receptor, in combination with trastuzumab and docetaxel for treatment of metastatic HER-2-positive breast cancer. There is significant interest in dual targeting of HER-2 and multiple trials are ongoing in the metastatic and neoadjvuant settings.
SPECIAL CLINICAL SITUATIONS
Unilateral Nipple Discharge
Nipple discharge is a finding that can be seen in a number of clinical situations. It may be suggestive of cancer if it is spontaneous, unilateral, localized to a single duct, present in women ≥40 years of age, bloody, or associated with a mass. A trigger point on the breast may be present so that pressure around the nipple-areolar complex induces discharge from a single duct. In this circumstance, mammography and ultrasound are indicated for further evaluation. A ductogram also can be useful and is performed by cannulating a single discharging duct with a small nylon catheter or needle and injecting 1.0 mL of water-soluble contrast solution. Nipple discharge associated with a cancer may be clear, bloody, or serous. Testing for the presence of hemoglobin is helpful, but hemoglobin may also be detected when nipple discharge is secondary to an intraductal papilloma or duct ectasia. Definitive diagnosis depends on excisional biopsy of the offending duct and any associated mass lesion. A 3.0 lacrimal duct probe can be used to identify the duct that requires excision. Another approach is to inject methylene blue dye within the duct after ductography. The nipple must be sealed with collodion or a similar material so that the blue dye does not discharge through the nipple but remains within the distended duct facilitating its localization. Needle localization biopsy is performed when there is an associated mass that lies >2.0 to 3.0 cm from the nipple.
Bilateral Nipple Discharge
Nipple discharge is suggestive of a benign condition if it is bilateral and multiductal in origin, occurs in women ≤39 years of age, or is milky or blue-green. Prolactin-secreting pituitary adenomas are responsible for bilateral nipple discharge in <2% of cases. If serum prolactin levels are repeatedly elevated, plain radiographs of the sellaturcica are indicated and thin section CT scan is required. Optical nerve compression, visual field loss, and infertility are associated with large pituitary adenomas.
Axillary Lymph Node Metastases in the Setting of an Unknown Primary Cancer
A woman who presents with an axillary lymph node metastasis that is consistent with a breast cancer metastasis has a 90% probability of harboring an occult breast cancer.303 However, axillary lymphadenopathy is the initial presenting sign in only 1% of breast cancer patients. Fine-needle aspiration biopsy or core-needle biopsy can be used to establish the diagnosis when an enlarged axillary lymph node is identified. When metastatic cancer is found, immunohistochemical analysis may classify the cancer as epithelial, melanocytic, or lymphoid in origin. The presence of hormone receptors (estrogen or progesterone receptors) suggests metastasis from a breast cancer but is not diagnostic. The search for a primary cancer includes careful examination of the thyroid, breast, and pelvis, including the rectum. The breast should be examined with diagnostic mammography, ultrasonography, and MRI to evaluate for an occult primary lesion. Further radiologic and laboratory studies should include chest radiography and liver function studies. Additional imaging of the chest, abdomen, and skeleton may be indicated if the extent of nodal involvement is consistent with stage III breast cancer. Suspicious findings on mammography, ultrasonography, or MRI necessitate breast biopsy. When a breast cancer is found, treatment consists of an axillary lymph node dissection with a mastectomy or preservation of the breast followed by whole-breast radiation therapy. Chemotherapy and endocrine therapy should be considered.
Breast Cancer During Pregnancy
Breast cancer occurs in 1 of every 3000 pregnant women, and axillary lymph node metastases are present in up to 75% of these women.304 The average age of the pregnant woman with breast cancer is 34 years. Fewer than 25% of the breast nodules developing during pregnancy and lactation will be cancerous. Ultrasonography and needle biopsy specimens are used in the diagnosis of these nodules. Mammography is rarely indicated because of its decreased sensitivity during pregnancy and lactation; however, the fetus can be shielded if mammography is needed. Approximately 30% of the benign conditions encountered will be unique to pregnancy and lactation (galactoceles, lobular hyperplasia, lactating adenoma, and mastitis or abscess). Once a breast cancer is diagnosed, complete blood count, chest radiography (with shielding of the abdomen), and liver function studies are performed.
Because of the potential deleterious effects of radiation therapy on the fetus, radiation cannot be considered until the fetus is delivered. A modified radical mastectomy can be performed during the first and second trimesters of pregnancy, even though there is an increased risk of spontaneous abortion after first-trimester anesthesia. During the third trimester, lumpectomy with axillary node dissection can be considered if adjuvant radiation therapy is deferred until after delivery. Lactation is suppressed. Chemotherapy administered during the first trimester carries a risk of spontaneous abortion and a 12% risk of birth defects. There is no evidence of teratogenicity resulting from administration of chemotherapeutic agents in the second and third trimesters. For this reason, many clinicians now consider the optimal strategy to be delivery of chemotherapy in the second and third trimesters as a neoadjuvant approach, which allows local therapy decisions to be made after the delivery of the baby. Pregnant women with breast cancer often present at a later stage of disease because breast tissue changes that occur in the hormone-rich environment of pregnancy obscure early cancers. However, pregnant women with breast cancer have a prognosis, stage by stage, that is similar to that of nonpregnant women with breast cancer.
Fewer than 1% of all breast cancers occur in men.305,306 The incidence appears to be highest among North Americans and the British, in whom breast cancer constitutes as much as 1.5% of all male cancers. Jewish and African American males have the highest incidence. Male breast cancer is preceded by gynecomastia in 20% of men. It is associated with radiation exposure, estrogen therapy, testicular feminizing syndromes, and Klinefelter’s syndrome (XXY). Breast cancer is rarely seen in young males and has a peak incidence in the sixth decade of life. A firm, nontender mass in the male breast requires investigation. Skin or chest wall fixation is particularly worrisome.
DCIS makes up <15% of male breast cancer, whereas infiltrating ductal carcinoma makes up >85%. Special-type cancers, including infiltrating lobular carcinoma, have occasionally been reported. Male breast cancer is staged in the same way as female breast cancer, and stage by stage, men with breast cancer have the same survival rate as women. Overall, men do worse because of the more advanced stage of their cancer (stage II, III or IV) at the time of diagnosis. The treatment of male breast cancer is surgical, with the most common procedure being a modified radical mastectomy. SLN dissection has been shown to be feasible and accurate for nodal assessment in men presenting with a clinically node-negative axilla. Adjuvant radiation therapy is appropriate in cases in which there is a high risk for local-regional recurrence. Approximately 80% of male breast cancers are hormone receptor positive, and adjuvant tamoxifen is considered. Systemic chemotherapy is considered for men with hormone receptor-negative cancers and for men with large primary tumors, multiple positive nodes, and locally advanced disease.
The nomenclature, presentation, and diagnosis of phyllodes tumors (including cystosarcoma phyllodes) have posed many problems for surgeons.307 These tumors are classified as benign, borderline, or malignant. Borderline tumors have a greater potential for local recurrence.
Mammographic evidence of calcifications and morphologic evidence of necrosis do not distinguish between benign, borderline, and malignant phyllodes tumors. Consequently, it is difficult to differentiate benign phyllodes tumors from the malignant variant and from fibroadenomas. Phyllodes tumors are usually sharply demarcated from the surrounding breast tissue, which is compressed and distorted. Connective tissue composes the bulk of these tumors, which have mixed gelatinous, solid, and cystic areas. Cystic areas represent sites of infarction and necrosis. These gross alterations give the gross cut tumor surface its classical leaf-like (phyllodes) appearance. The stroma of a phyllodes tumor generally has greater cellular activity than that of a fibroadenoma. After microdissection to harvest clusters of stromal cells from fibroadenomas and from phyllodes tumors, molecular biology techniques have shown the stromal cells of fibroadenomas to be either polyclonal or monoclonal (derived from a single progenitor cell), whereas those of phyllodes tumors are always monoclonal.
Most malignant phyllodes tumors (Fig. 17-38) contain liposarcomatous or rhabdomyosarcomatous elements rather than fibrosarcomatous elements. Evaluation of the number of mitoses and the presence or absence of invasive foci at the tumor margins may help to identify a malignant tumor. Small phyllodes tumors are excised with a margin of normal-appearing breast tissue. When the diagnosis of a phyllodes tumor with suspicious malignant elements is made, reexcision of the biopsy specimen site to ensure complete excision of the tumor with a 1-cm margin of normal-appearing breast tissue is indicated. Large phyllodes tumors may require mastectomy. Axillary dissection is not recommended because axillary lymph node metastases rarely occur.
A. Malignant phyllodes tumor (cystosarcomaphyllodes). B. Histologic features of a malignant phyllodes tumor (hematoxylin and eosin stain, ×100).
Inflammatory Breast Carcinoma
Inflammatory breast carcinoma (stage IIIB) accounts for <3% of breast cancers. This cancer is characterized by the skin changes of brawny induration, erythema with a raised edge, and edema (peaud’orange).308 Permeation of the dermal lymph vessels by cancer cells is seen in skin biopsy specimens. There may be an associated breast mass (Fig. 17-39). The clinical differentiation of inflammatory breast cancer may be extremely difficult, especially when a locally advanced scirrhous carcinoma invades dermal lymph vessels in the skin to produce peaud’orange and lymphangitis (Table 17-15). Inflammatory breast cancer also may be mistaken for a bacterial infection of the breast. More than 75% of women who have inflammatory breast cancer present with palpable axillary lymphadenopathy, and distant metastases also are frequently present. A positron emission tomography (PET)-computed tomography (CT) scan should be considered at the time of diagnosis to rule out concurrent metastatic disease. A report of the SEER program described distant metastases at diagnosis in 25% of white women with inflammatory breast carcinoma.
Inflammatory breast carcinoma. Stage IIIB cancer of the breast with erythema, skin edema (peaud’orange), nipple retraction, and satellite skin nodules.
Table 17-15Inflammatory vs. noninflammatory breast cancer ||Download (.pdf) Table 17-15 Inflammatory vs. noninflammatory breast cancer
Dermal lymph vessel invasion is present with or without inflammatory changes.
Inflammatory changes are present without dermal lymph vessel invasion.
Cancer is not sharply delineated.
Cancer is better delineated.
Erythema and edema frequently involve >33% of the skin over the breast.
Erythema is usually confined to the lesion, and edema is less extensive.
Lymph node involvement is present in >75% of cases.
Lymph nodes are involved in approximately 50% of the cases.
Distant metastases are present in 25% of cases.
Distant metastases are less common at presentation.
Distant metastases are more common at initial presentation.
Surgery alone and surgery with adjuvant radiation therapy have produced disappointing results in women with inflammatory breast cancer. However, neoadjuvant chemotherapy with ananthracycline-containing regimen may affect dramatic regressions in up to 75% of cases. Tumor should be assessed for HER-2 and hormone receptors with treatment dictated based on receptor status. Modified radical mastectomy is performed after demonstrated response to systemic therapy to remove residual cancer from the chest wall and axilla. Adjuvant chemotherapy may be indicated depending on final pathologic assessment of the breast and regional nodes. Finally, the chest wall and the supraclavicular, internal mammary, and axillary lymph node basins receive adjuvant radiation therapy. This multimodal approach results in 5-year survival rates that approach 30%. Patients with inflammatory breast cancer should be encouraged to participate in clinical trials.
Squamous Cell (Epidermoid) Carcinoma
Squamous cell (epidermoid) carcinoma is a rare cancer that arises from metaplasia within the duct system and generally is devoid of distinctive clinical or radiographic characteristics.309 Regional metastases occur in 25% of patients, whereas distant metastases are rare.
Adenoid cystic carcinoma is very rare, accounting for <0.1% of all breast cancers. It is typically indistinguishable from adenoid cystic carcinoma arising in salivary tissues. These cancers are generally 1 to 3 cm in diameter at presentation and are well circumscribed. Axillary lymph node metastases are rare, but deaths from pulmonary metastases have been reported.
Apocrine carcinomas are well-differentiated cancers that have rounded vesicular nuclei and prominent nucleoli. There is a very low mitotic rate and little variation in cellular features. However, apocrine carcinomas may display an aggressive growth pattern.
Sarcomas of the breast are histologically similar to soft tissue sarcomas at other anatomic sites. This diverse group includes fibrosarcoma, malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, malignant schwannoma, rhabdomyosarcoma, osteogenic sarcoma, and chondrosarcoma. The clinical presentation is typically that of a large, painless breast mass with rapid growth. Diagnosis is by core-needle biopsy or by open incisional biopsy. Sarcomas are graded based on cellularity, degree of differentiation, nuclear atypia, and mitotic activity. Primary treatment is wide local excision, which may necessitate mastectomy. Axillary dissection is not indicated unless there is biopsy proven lymph node involvement. Angiosarcomas are classified as de novo, as postradiation, or as arising in association with postmastectomy lymphedema. In 1948, Stewart and Treves described lymphangiosarcoma of the upper extremity in women with ipsilateral lymphedema after radical mastectomy.310 Angiosarcoma is now the preferred name. The average interval between modified radical or radical mastectomy and the development of an angiosarcoma is 7 to 10 years. Sixty percent of women developing this cancer have a history of adjuvant radiation therapy. Forequarter amputation may be necessary to palliate the ulcerative complications and advanced lymphedema.
Primary lymphomas of the breast are rare, and there are two distinct clinicopathologic variants. One type occurs in women ≤39 years of age, is frequently bilateral, and has the histologic features of Burkitt’s lymphoma. The second type is seen in women ≥40 years of age and is usually of the B-cell type. Breast involvement by Hodgkin’s lymphoma has been reported. An occult breast lymphoma may be diagnosed after detection of palpable axillary lymphadenopathy. Treatment depends on the stage of disease. Lumpectomy or mastectomy may be required. Axillary dissection for staging and for clearance of palpable disease is appropriate. Recurrent or progressive local-regional disease is best managed by chemotherapy and radiation therapy. The prognosis is favorable, with 5- and 10-year survival rates of 74% and 51%, respectively.