Breast Cancer

Breast Anatomy The Breast Anatomy The Breast Duct Anatomy A: Ducts B: Lobules C: Dilated section of duct to hold milk D: Nipple E: Fat F: Pectoralis major muscle G: Chest wall/rib cage A: Normal duct cells B: Basement membrane C: Lumen (center of duct) The Axillary Lymph Nodes A: Pectoralis major muscle. B: Axillary lymph nodes: levels I. C: Axillary lymph nodes: levels II. D: Axillary lymph nodes: levels III. E: Aupraclavicular lymph nodes. F: Internal mammary lymph nodes.

Life Extension Breast Health Formula (60 vegetarian capsules)

Clinical Features

Clinical Investigations

Medical Therapy

Ductal carcinoma in situ

Approximately 85% of DCIS is detected mammographically, and this represents 20-30% of mammographically detected breast cancer. The risk of developing invasive cancer is approximately 40% in the ipsilateral breast and 5% in the contralateral breast. Regardless of the initial treatment modality, 50% of recurrences are invasive carcinoma.

Mastectomy cures 98-99% of all types of DCIS, with a recurrence rate of only 1-2%. Most recently, lumpectomy with RT was shown to yield local recurrence rates of 7-13.4%, compared with 26.8-43% for local excision alone. Furthermore, the addition of tamoxifen resulted in a 44% decrease of invasive breast cancer in the ipsilateral breast and a 52% decrease of invasive breast cancer in the contralateral breast.

Predictors of recurrence in patients undergoing BCS for DCIS are as follows:

• Residual microcalcifications: Risk of relapse is 100%.
• Comedo necrosis
• Positive margins: For margins less than 1 mm, the recurrence rate is 25%. For margins of 1-9 mm, the recurrence rate is 15%. For margins greater than 1 cm, the recurrence rate is 3%.
• Age younger than 50 years
• Bloody discharge

Lobular carcinoma in situ

This lesion is usually an incidental finding in breast biopsy specimens. LCIS is not a cancer; it is an indicator for increased risk for breast cancer. This risk is estimated at 1-1.5% per year and 20-30% over a lifetime. Of invasive carcinoma developing in this setting, 50% is ductal carcinoma; the other 50% is lobular carcinoma.

Patients may be observed or offered participation in a chemoprevention trial. Bilateral simple mastectomy with immediate reconstruction is the recommended surgery should the patient elect a radical treatment. Chemotherapy and RT have no role in the treatment of this lesion.

Treatment of invasive disease

Modern treatment of breast cancer is based on a multimodality approach combining surgery, chemotherapy, HT, and RT. Treatment is tailored for an individual patient based on tumor size, axillary lymph node involvement, ER and PR status (the most important variables identified by many historical studies), histologic tumor type, standardized pathologic grade, and menopausal status. The 2000 US National Institutes of Health Consensus Conference updated adjuvant therapy guidelines for breast cancer.

Adjuvant hormonal therapy

Adjuvant HT is indicated only in the presence of hormone receptors (ER and/or PR) on cancer tissue assessed using IHC. Adjuvant tamoxifen has shown a 50% decrease in the risk of breast cancer recurrence and a 28% decrease in breast cancer mortality, while ovarian ablation produced benefits similar to certain chemotherapies (20-25%) in this population.

In 2 cooperative trials (NSABP 23, Intergroup trial 0102), the addition of tamoxifen to chemotherapy was not associated with improvement in disease-free survival and overall survival in patients with ER-negative tumors and was even detrimental in premenopausal patients with ER-negative tumors. Therefore, HT is indicated only in case of ER and/or PR positivity, regardless of age, menopausal status, lymph node status, or tumor size.

The goal of HT in breast cancer is to induce an estrogen deprivation state at the tumor level. This may be achieved by (1) receptor blockade using one of the selective estrogen receptor modulators, such as tamoxifen or toremifene; (2) suppression of estrogen synthesis by aromatase inhibitors (eg, anastrozole, letrozole, exemestane) in postmenopausal women or by luteinizing hormone-releasing hormone analogues (eg, goserelin) in premenopausal women; or (3) ovarian ablation by surgical oophorectomy or external beam radiation therapy in premenopausal women.

Tamoxifen has been the most common form of adjuvant HT used to date. It can be used both in pre and post menopausal women. However, the recent publication of the results of many large aromatase inhibitor (AI) trials (ATAC, BIG 1-98, examestene trial) has shown that AIs are superior to tamoxifen as adjuvant HT in postmenopausal women. Anastrozole and letrozol are approved for use in first line hormonal therapy for HR-positive postmenopausal women and examestene is approved for use sequentially after 2-3 years of tamoxifen. When tamoxifen is chosen, administer 20 mg/d for 5 years. In asymptomatic women, no special screening procedures (eg, transvaginal ultrasound, endometrial biopsies) for endometrial cancer are recommended. The dose of anastrozole is 1 mg a day, of letrozol 2.5 mg and of examestene 25 mg a day.

The Early Breast Cancer Trialists' Collaborative Group's overview analysis suggests that ovarian ablation is effective as adjuvant HT for premenopausal receptor-positive breast cancer patients regardless of nodal status. Premenopausal patients who receive chemotherapy and maintain their ovarian function may benefit from ovarian ablation. If the patient is younger than 50 years and there is a question about her ovarian function, FSH/LH and estradiol should be checked to document her menopausal status.

Adjuvant chemotherapy

Combination chemotherapy is superior to single agents in the adjuvant setting. The body of knowledge about adjuvant chemotherapy for breast cancer has benefited from the serial updates of the Oxford Overview analysis and from other large randomized trials, which have shown slight but statistically significant superiority of anthracycline-containing regimens over traditional CMF. Adjuvant chemotherapy results in an approximately 25% decrease of breast cancer mortality. However, the determination of the anthracycline-containing regimen of choice is still under investigation.

Doxorubicin (Adriamycin) and cyclophosphamide (AC) has a threshold effect; thus, doses greater than 60 mg/m² and 600 mg/m², respectively, are of no additional benefit. The results of 3 large US trials (NSABP B22 and B25, Cancer and Leukemia Group B 9344) did not support any role for dose intensification of the AC combination. However, 2 other studies, one French (French Adjuvant Study Group -05) and the other Canadian, showed that when epirubicin was escalated in the fluorouracil-epirubicin-cyclophosphamide (FEC) combination, disease-free survival and overall survival were significantly improved in operable breast cancer with positive axillary lymph nodes.

High-dose chemotherapy with stem cell or bone marrow support did not prove superior to standard chemotherapy and is best reserved for clinical trials.

Results from two trials (Cancer and Leukemia Group B 9344 and NSABP-B28) exploring the role of taxanes in the adjuvant setting were encouraging. CALGB-9344 had a 3x2 factorial design with patients randomized to receive doxorubicin at 60, 75, or 90 mg/m followed by paclitaxel at 175 mg/m² or no additional therapy. NSABP-B28 had similar design except that the dose of doxorubicin was not escalated and the dose of paclitaxel was 225 mg/m². From the first trial it was established unequivocally that doxorubicin dose escalation does not improve outcome while the addition of paclitaxel results in small but statistically significant improvement of both the risk of relapse and the risk of death. In NSABP-B28, relapse free survival was significantly improved by the addition of paclitaxel while the data about survival are not available yet.

In patients with node-negative, early-stage disease (stages I, IIA, and IIB), chemotherapy is not indicated if the tumor is smaller than 0.5 cm, regardless of the histologic subtype. In persons with invasive ductal and lobular carcinomas, tumors measuring 0.6-1 cm require chemotherapy only if they were associated with unfavorable features (eg, angiolymphatic invasion, high S-phase, high nuclear grade, high histologic grade), while all tumors larger than 1 cm require adjuvant chemotherapy alone (hormone-receptor negative) or in combination with tamoxifen (hormone-receptor positive). In patients with other histologic types (ie, tubular, colloid, medullary, adenoid), chemotherapy is indicated only for tumors larger than 3 cm. It may be considered in those from 1-2.9 cm, and it is not indicated for tumors smaller than 1 cm.

In patients with node-positive, early-stage disease, adjuvant chemotherapy with or without adjuvant HT is the mainstay of treatment. Anthracycline-containing chemotherapy, such as doxorubicin (Adriamycin) (60 mg/m²) and cyclophosphamide (600 mg/m²), administered for 4 cycles is the treatment of choice. Many oncologists consider this treatment insufficient and opt for 2 more cycles of the same treatment or 2-4 cycles of paclitaxel (175 mg/m²).

In persons with advanced-stage disease (stage IIIA and IIIB), the same regimen of AC for 4 cycles followed by at least 2 more cycles of the same treatment or 4 cycles of a taxane is recommended after surgical treatment. Neoadjuvant chemotherapy may be offered to patients with this stage.

The role of neoadjuvant chemotherapy is being intensively investigated. The NSABP B-18 trial compared the effect of preoperative AC for 4 cycles to the same regimen postoperatively in subjects with early-stage breast cancer. Pathologic node-negativity of 60% and BCS of 68% could be achieved in the preoperative AC group compared with 42% and 60%, respectively, in the postoperative AC group. Five-year disease-free survival and overall survival rates for those who achieved pathologic complete response were 84% and 87% compared with 72% and 78%, respectively, in patients who had residual disease.

Based on these encouraging results, NSABP started its B-27 trial to address the question related to the role of 4 cycles of preoperative or postoperative docetaxel added to 4 AC cycles. The use of preoperative docetaxel almost doubled the pathologically confirmed complete remission rate compared with the AC arm (25.6% vs 13.7%).

Because the role of neoadjuvant therapy is not fully established, participation in clinical trials should be encouraged. In ER- and/or PR-positive tumors, neoadjuvant tamoxifen or letrozole may achieve the same magnitude of response as chemotherapy but with longer time to response. Although the neoadjuvant approach does not seem to prolong survival, its theoretical advantages include downstaging the tumor, in vivo testing of the chemosensitivity of the tumor, and allowing BCS.

The treatment of metastatic disease is mainly medical. In postmenopausal patients with ER- and/or PR-positive tumors, the use of tamoxifen or an aromatase inhibitor (eg, anastrozole, letrozole, exemestane) is the standard of care for bone disease and limited visceral disease. In many cases, at least a partial response can be achieved. Patients who progress on first-line HT may still respond to second- or third-line HT, aromatase inhibitors, and megestrol acetate, respectively.

ER down-regulators are a promising new class of HT agents that may have some efficacy if the previous treatments fail. In premenopausal women with ER- and/or PR-positive breast cancer, ovarian ablation and tamoxifen are the mainstays of treatment. Ovarian ablation can be achieved by medical (eg, luteinizing hormone-releasing hormone analogues such as goserelin, leuprolide, buserelin, and triptorelin), surgical (ie, bilateral oophorectomy), or RT methods.

Chemotherapy is indicated for patients with advanced visceral disease (visceral crisis) and those with hormone-refractory or hormone-insensitive tumors. The goals of chemotherapy in this setting are palliative and include control of symptoms, control of disease progression, and prolongation of life. The best response rates are obtained with first-line therapy and combination regimens. However, regardless of the response rates achieved with these therapies (including high-dose chemotherapy with autologous stem cell support), survival is not affected in most cases.

In 2001, Slamon and Pegram reported a survival advantage for the combination of chemotherapy and trastuzumab over chemotherapy alone in women with HER2 -positive metastatic breast cancer.

Table 1 Single-Agent Chemotherapy for Metastatic Breast Cancer

Table 2  Adjuvant Chemotherapy Regimens for Breast Cancer

Predictors of poor response to chemotherapy in patients with metastatic breast cancer are poor performance status, multiple and/or visceral sites of disease, short disease-free intervals, and failure to respond to prior chemotherapy. Because the goals of chemotherapy in patients with metastatic breast cancer are palliative, many authorities recommend the sequential use of single chemotherapeutic agents rather than combinations in order to limit toxicity. Taxanes, anthracyclines, oral fluoropyrimidines, vinorelbine, and gemcitabine are the most effective drugs used in this setting.

Trastuzumab, a monoclonal antibody directed against the extracellular domain of the HER2/neu receptor, has shown significant antitumor activity in patients with metastatic breast cancer overexpressing HER2/neu. Response rates of 30-35% have been observed in patients with metastatic breast cancer who are receiving single-agent trastuzumab as a first-line therapy. The relative risk of death was decreased by 20% with a median follow-up of 30 months when trastuzumab was used in combination with chemotherapy. However, when combined with doxorubicin, a significant increase in cardiotoxicity was noted. For this reason, the current recommendation is to avoid trastuzumab in combination with or after doxorubicin.

The mechanism of action of trastuzumab is still debated. Trastuzumab induces down-regulation of HER2/neu and prevents its heterodimerization, reestablishing breast cancer cell sensitivity to HT and chemotherapy. As a result of this down-regulation, p27 is induced, resulting in cell-cycle arrest in the G1 phase. Furthermore, trastuzumab binds to the receptor at a site where the extracytoplasmic domain (ECD) is usually cleaved by metalloproteinases. The ECD cleavage results in a constitutively active truncated receptor and a more aggressive phenotype; this would be prevented by binding to trastuzumab. Finally, trastuzumab may induce antibody-dependent cytotoxicity, resulting in cell death.

Four large multicenter trials were conducted with trastuzumab in the adjuvant setting in patients with HER2/neu-positive breast cancer (NSABP B31, NCCTG N9831, The HERA trial and BCIRG 06). A combined analysis of the first two trials showed dramatic improvement of DFS in the group randomized to receive trastuzumab with chemotherapy consisting of AC x 4 followed by T x 4.

Radiotherapy

RT reduces the risk of local recurrence and has the potential to decrease long-term mortality from breast cancer. Although certain studies have shown that RT following chemotherapy results in better long-term survival rates than the opposite, recent updates from Bellon et al and the Joint Center randomized trial showed no significant differences between the CT-first and RT-first arms in any endpoint studied. A reduction of approximately 20% in local recurrence correlates with an absolute reduction of approximately 5% in long-term mortality from breast cancer 10-15 years later.

RT to the breast (with or without the supraclavicular area) is indicated after lumpectomy in persons with early-stage breast cancer as an integral part of the treatment plan, and it is indicated after mastectomy in the presence of a large tumor mass (>5 cm), positive margins, and 4 or more lymph nodes positive for disease.

The role of axillary RT after radical ALND is debated. Many experts believe that RT is best avoided after complete dissection of the axilla for level I, II, and III nodes (RM and modified RM). A 6- to 8-fold increase in the incidence of lymphedema in the ipsilateral arm was reported with the combined modality.

Surgical Treatment

Procedures

RM is the en bloc resection of the breast, the overlying skin, the pectoralis muscles, and all of the axillary contents (level I, II, and III dissection). Extended RM is RM with removal of the internal mammary nodes. Both procedures are rarely performed in current practice. In addition to their mutilating effects, they result in functional impairment as a result of neurologic and lymphatic vessel damage. Resection of the involved portion of the muscle is satisfactory even when the tumor abuts or invades the pectoral fascia or when the muscle fascia was violated at the time of biopsy.

Modified RM implies the removal of breast tissue, the underlying fascia of the pectoralis major muscle, and some of the axillary lymph nodes. The nipple-areola complex and the area around the biopsy incision must be removed, but the remainder of the skin of the breast can be preserved.

Total mastectomy removes the entire breast. Both pectoralis muscles and the axillary nodes are preserved.

Skin-sparing mastectomy removes the breast parenchyma, the previous biopsy site(s), and the skin overlying superficial tumors through a periareolar incision. Thus, the breast envelope is preserved, allowing immediate reconstruction with improved cosmetic results. Skin-sparing mastectomy can be coupled with SLNB.

BCS (lumpectomy) removes the tumor with 0.5-1 cm of normal tissue. It is often coupled with ipsilateral axillary lymph node sampling and, increasingly, with SLNB. Quadrantectomy is the removal of the quadrant containing the cancer with the overlying skin and underlying pectoral fascia.

ALND, when performed in a 2-cm primary breast cancer to levels I and II, reduces the probability for regional recurrence from 20% to approximately 3%.

Regarding SLNB, the combined use of a radionuclide and a blue dye increases the detection rate of the SLN. Isosulfan blue (Lymphazurin) is the most commonly used blue dye. Five mL of isosulfan blue are injected into the parenchyma, and the injection site is gently massaged for 3-5 minutes before the SLNB procedure is performed. Technetium sulfur colloid, the radionuclide of choice, is used at a dose of 0.1-1 mCi. The isotope is injected into the parenchyma 1-2 hours before the procedure. The SLN is preoperatively localized using a handheld gamma probe.

Preoperative Details

Conduct a thorough preoperative assessment, and discuss with the patient and family the risks related to the cancer itself or to any comorbid conditions that may impact the intended surgery. Focus this discussion on prognostic factors, therapeutic options for the stage of the disease (with their expected benefits and adverse effects), and alternatives to surgery if available.

With young patients or those who desire a reconstruction, also discuss immediate versus delayed plastic surgery. For all patients with locally advanced disease, seek consultation with a medical oncologist to consider the role of neoadjuvant chemotherapy.

Intraoperative Details

Whenever BCS is performed, the surgeon has the responsibility to ensure that all involved tissues are removed. Frozen-section studies are performed perioperatively, followed by permanent-section studies. Perform total mastectomy if the margins are not clear or if the specimen contains multicentric disease.

Lumpectomy

Lumpectomy or wide local excision may be performed with the patient under local anesthesia if no axillary node dissection is planned. General anesthesia is preferred for large excisions or if axillary dissection is intended. A long, curvilinear incision is placed directly over the lesion in such a way as to allow its inclusion in a future mastectomy incision if the margins are positive.

A radial incision is better suited for lesions located far laterally or in the areolar area. The dissection is performed around the palpable tumor, which is removed with 1-1.5 cm of grossly normal tissue. In cases of a nonpalpable lesion, remove 2-3 cm of tissue around the localization wire.

Exercise care for proper orientation and margin inking of the specimen to ensure appropriate pathological study of the margins. Reexcision can be performed immediately if instantaneous study results are available, or it can be performed later. Subcuticular closure is performed after appropriate hemostasis and approximation of deep tissues if the latter does not result in major deformity of the breast contour.

Axillary dissection

In axillary dissection, include level I and II lymph nodes and axillary fibrofatty tissue. Level III lymph nodes are preserved unless gross disease is present. The borders of the dissection are the axillary vein and the medial aspect of the pectoralis minor muscle superiorly, the latissimus dorsi muscle laterally, the pectoral muscles and the anterior serratus muscle medially, and the tail of the breast inferiorly.

Make a transverse incision in the lower third of the hair-bearing skin of the axilla; the incision can be extended posteriorly to the latissimus dorsi muscle for larger exposure. The dissection proceeds through the true axillary fat pad and its fascia to allow exposure of major pectoralis and latissimus dorsi muscles. Recognition of anatomical landmarks such as the axillary vein, the thoracodorsal bundle, and the long thoracic nerve help to maintain proper orientation and to preserve important structures.

Low-lying branches of the brachial plexus are preserved after identification of the axillary vein under the pectoralis major muscle medially. The thoracodorsal bundle is identified at its junction with either the axillary vein or the latissimus dorsi muscle. Medial to this bundle, the long thoracic vein is recognized lying on the chest wall.

Retraction is applied on the pectoralis major and latissimus dorsi muscles to ensure good exposure. The fat and the lymph nodes located medial to the thoracodorsal bundle are removed up to the level of the axillary vein, and then the dissection proceeds medially to level II fat and nodes beneath the pectoralis major muscle, where the medial pectoral nerve may be encountered.

Dissection of the axillary fat continues inferiorly along the anterior serratus muscle, where the long thoracic nerve is identified and preserved. Lastly, the axillary fat is released from its attachment to the tail of the breast by knife or electrocautery. Most surgeons drain the axilla after axillary dissection.

Sentinel lymph node biopsy

This procedure can be performed with the patient under local or general anesthesia. The isotope and the blue dye are injected 2 hours and 5 minutes before the procedure, respectively. Through an incision made below the "hot spot" identified by the gamma probe, the surgeon can identify a blue-green lymphatic representing the afferent lymphatic leading to the SLN.

The removed SLN is examined ex vivo using the gamma probe to determine its count, which serves as a reference for a reexamination of the axilla. Remove hot spots with counts exceeding 10% of the hottest ex vivo node. In patients undergoing lumpectomy, perform the SLNB before the lumpectomy; for those undergoing modified RM, perform the procedure during ALND before or after the mastectomy.

Mastectomy

Mastectomy (modified radical or simple) implies removing all the breast tissue and the overlying skin, including the nipple-areola complex, and leaving viable skin flaps. Whether a transverse or an upward-angled incision is chosen, include the nipple-areola complex and previous biopsy incisions in the excised area.

After determining upper and lower endpoints and while the breast is pulled firmly downward, a straight line is drawn to define the upper incision. The lower incision is similarly drawn while the breast is pulled upward.

Skin flaps are started by dissecting through the avascular plane between the subcutaneous fat and the breast tissue and are then followed down by dividing the Cooper ligaments. Perform the dissection medially to the sternum, inferiorly to the inframammary fold, laterally to the latissimus dorsi muscle, and superiorly to the clavicle. Include in the specimen the fascia of the pectoralis major muscle, which constitutes the deep margins of the dissection.

In a simple mastectomy, the dissection is stopped before the axillary fat pad is entered. In a modified RM, and according to the surgeon's preference, the dissection may start with the breast and proceed through the axilla or it may start in the axilla and finish in the breast. Avoid excessive hemostasis to preserve the viability of the flaps. Closure is performed without tension or redundant skin after placement of 2 closed suction drains.

Postoperative Details

Offer breast reconstruction to patients with breast cancer as an integral part of the multidisciplinary therapeutic approach. It may be immediate or delayed.

Immediate reconstruction is offered to patients with stage 0, I, or II disease. Its psychological, esthetic, and practical advantages outweigh its disadvantages, which mainly include the need for a multidisciplinary team collaborating during the same operative time and the absence of final histology results during surgery. Complications are similar to those of ablative surgery alone. Immediate reconstruction can be combined with any type of ablative surgery, including modified RM. Delayed reconstruction can be performed in all breast cancer stages. It usually follows chemotherapy and RT.

Two reconstructive techniques are used: implant insertion and autologous graft. Implants are made of a silicone shell filled with silicone gel or saline. Although the surgical procedure itself is short and easy, long-term complications are common and include capsular contracture/wrinkling, skin necrosis, and leakage (33%, 8.5%, and 6%, respectively). Because of this high rate of problems, multiple revisions are required, which can add significantly to the total cost. Implants are indicated for small- to medium-sized breasts, in women with poor general health, and in those with short life expectancy. They are contraindicated in patients who require chest wall RT, owing to the high rate of complications.

Although breast reconstruction using autologous tissue is more complex, its advantages far outweigh those of the implant. Esthetically, breast reconstruction results in a warm, soft texture of the breasts with good imitation of natural ptosis. Results are long-lasting, with a low rate of complications and subsequent procedures. Breast reconstruction is probably the only valid option for patients with partial mastectomy and those who require RT.

The most commonly used flaps are the pedicled latissimus dorsi myocutaneous flap, the thoracodorsal artery perforator skin-flat flap, the pedicled or free transverse rectus abdominis myocutaneous flap, the free deep inferior epigastric perforator skin-flat flap, the superior and inferior gluteus myocutaneous flap, and the free superior gluteal artery perforator skin-flat flap. The choice of the donor site and type of procedure depend not only on local conditions at the donor and recipient sites but also on the surgeon's experience.

Complications

Mastectomy

• Wound infection and abscess
• Necrosis of skin flap
• Paresthesia of chest wall
• Phantom breast syndrome
• Postsurgical pain syndrome
• Seroma
• Lymphedema

Axillary lymph node dissection

• Injury to or thrombosis of the axillary vein
• Seroma formation
• Lymphedema: The reported prevalence rate of lymphedema is approximately 11%, with extremes ranging from 5-30%. Extensive surgery, RT, and advanced age are recognized risk factors for arm edema. Although the risk may decrease with time, it does not completely disappear.
• Impairment of shoulder movements: Depending on whether the patient has received RT to the axilla, the incidence rate varies from 12-15% (RT) and 7-8% (no RT). Symptoms include decreased range of motion of the shoulder, a problem that may be improved with early participation in a physical therapy program.
• Damage to the brachial plexus, with chronic pain and varying degrees of decreased grip strength occurring in up to 15% of patients and lasting for more than a year after surgery
• Chest wall pain

Chemotherapy

• Cyclophosphamide: Adverse effects may include hemorrhagic cystitis, and amenorrhea.
• Methotrexate: Adverse effects may include liver toxicity, increased toxicity in the presence of pleural effusion, and ascites.
• Fluorouracil: Adverse effects may include mucositis, hand-foot syndrome, and cerebellar ataxia.
• Doxorubicin: Adverse effects may include myocardial dysfunction, alopecia, nausea, vomiting, mucositis, and neutropenia.
• Paclitaxel: Adverse effects may include myelosuppression, peripheral neuropathy (less common if <170 mg/m² is used), hypersensitivity reaction (premedication with steroids, H1- and H2-receptor blockers), cardiac toxicity, alopecia, mucositis, nausea, vomiting, and typhlitis.
• Docetaxel: Adverse effects may include myelosuppression, mucositis, conjunctivitis, edema due to capillary leak syndrome (>80% of patients if not medicated; <10% if premedicated with steroids), hypersensitivity reactions, neurotoxicity (less frequent than with paclitaxel), nausea, vomiting, and alopecia.

Radiation therapy

• Necrosis of the breast soft tissue, prolonged breast edema, rib fracture (low rates, 1-3%)
• Decreased shoulder mobility (low rates, 1-3%)
• Brachial plexopathy with paresthesia and arm pain (low rates, 1-3%)
• Lymphedema
• Angiosarcoma: The 30-year cumulative risk is lower than 1%, with a peak incidence at 6 years.
• Lung cancer: Ipsilateral lung cancer may occur, with an increased risk in persons who smoke.
• Coronary artery disease: The risk has significantly decreased with newer RT techniques.
• Symptomatic pneumonitis: It is relatively infrequent, affecting 3-6% of women treated with RT for breast cancer. Patients present 3-12 months after competition of RT with dry cough, dyspnea, and low-grade fever. Chest radiographs may reveal intersitial infiltrate in the ipsilateral lung, which can evolve to fibrosis.

Adverse effects of tamoxifen

• Endometrial cancer: This rare complication occurs in 2 of every 1000 women receiving tamoxifen. Most of these cases are detected at an early stage and are easily cured by surgery. Other than yearly gynecologic examinations in asymptomatic women, the National Cancer Institute and the American Society of Obstetricians and Gynecologists recommend prompt evaluation with endometrial biopsy in women on tamoxifen who experience vaginal bleeding.
• Perimenopausal symptoms: Hot flashes and mood changes may occur in women on tamoxifen and occasionally are very severe, thus posing a serious threat to the woman's quality of life. Selective serotonin uptake inhibitors have been used with some success to treat these symptoms.
• Cataracts: These have also been reported in women receiving tamoxifen, justifying a yearly eye examination.

Adverse effects of trastuzumab

• Cardiac toxicity: In the phase III trial, trastuzumab alone resulted in cardiac dysfunction in 7% (class III/IV, 1.5%) of cases. The prevalence rate increased to 11% when trastuzumab was administered with paclitaxel (class III/IV, 0%). With the combination of anthracycline and cyclophosphamide, the prevalence rate increased to 28% (class III/IV, 6%). Apparently, the combination of an anthracycline and trastuzumab is particularly cardiotoxic. The mechanism of this dysfunction is yet to be defined. Although HER2/neu is minimally expressed on the cardiomyocytes, trastuzumab-induced phosphorylation of HER2 has been documented in vitro and is associated with cytoskeletal infrastructure dysfunction, which seems to be the underlying mechanism. These abnormalities may be reversed by adding neuregulin to the culture milieu. Clinically, trastuzumab-induced cardiomyopathy is partly reversible by medical therapy.
• Fever, chills, nausea, vomiting, and pain with first infusion: These are relatively common but become infrequent with subsequent infusions.

Prognosis

Controversies

The selective estrogen receptor modulator family, headed by tamoxifen, has been enlarged by the addition of new members (ie, toremifene, raloxifene, arzoxifene, lasofoxifene, idoxifene, EM-652, GW5638). Some have received approval for the same indications as tamoxifen (toremifene), and others are still the subjects of intense investigation. The introduction of aromatase inhibitors to the armamentarium of HT, first in the metastatic setting and more recently in the adjuvant setting, has opened new horizons for this modality. The new class of selective estrogen receptor down-regulators is being evaluated in clinical trials, and results are promising. Lastly, the rehabilitation of ovarian ablation with the use of luteinizing hormone-releasing hormone analogue has added another layer of complexity to modern HT for breast cancer.

The publication of the results of many aromatase inhibitor clinical trials including the ATAC, BIG 1-98 and the examestene trials evaluating the role or anastrozole, letrozol and examestene, respectively has announced the end of the tamoxifen domination era in the adjuvant setting. Furthermore, aromatase inhibitors have shown the capability to significantly reduce the prevalence of new contralateral breast primaries, paving the way for their use in chemoprevention trials. However, the following questions must be addressed.

• Which selective estrogen receptor modulators will be most effective in adjuvant and prevention settings?
• What is the role of selective estrogen receptor down-regulators?
• Which aromatase inhibitor is the best adjuvant therapy for breast cancer and if these agents are equivalent in terms of efficacy are they different in terms of toxicity?
• Using modern biotechnology (ie, genomics, proteomics), will it be possible to predict the responsiveness to any of these hormonal therapies?
• Will prolonged treatment of aromatase inhibitors beyond 5 years be superior to 5 years of therapy (more than 5 years of tamoxifen is not superior to 5 year) ?
• What is the best sequence to provide these patients with the longest survival possible?
• What are the patterns of resistance to HT, and are there methods available to overcome them?
• Will long-term use of aromatase inhibitors result in an increased prevalence of skeletal or other complications?

The overview analysis from the Early Breast Cancer Trialists' Collaborative Group has shown that ovarian ablation results in significant improvement of disease-free survival and overall survival, similar to cytotoxic chemotherapy. Because chemotherapy itself results in ovarian failure in 30-40% of patients younger than 40 years and in 70-90% of patients older than 40 years, the relative contribution of chemotherapy and ovarian ablation is difficult to determine. Several ongoing adjuvant trials are examining the role of ovarian ablation versus chemotherapy, the role of combined chemotherapy and ovarian ablation, and, lastly, the role of total estrogen ablation using tamoxifen and ovarian ablation.

Chemotherapy

Several concepts are being explored in this area.

The precise role of taxanes in the adjuvant setting is still awaiting the results of completed (ie, Breast Cancer International Research Group 001, Eastern Cooperative Oncology Group 2197) or ongoing trials. Three ongoing adjuvant trials are examining the role of sequential administration of taxanes following AC chemotherapy in early-stage breast cancer (Cancer and Leukemia Group B 9344, NSABP B-28, Eastern Cooperative Oncology Group 1199). Four other adjuvant trials are exploring the potential of doxorubicin/paclitaxel combinations (Breast Cancer International Research Group 001, Eastern Cooperative Oncology Group 2197, NSABP B-30, Breast Cancer International Research Group 005). Three trials are testing the effect of sequential anthracycline-containing regimens and paclitaxel in the neoadjuvant setting (NSABP B-27, M.D. Anderson Cancer Center, Aberdeen).

Many trials are addressing the role of trastuzumab in the adjuvant setting. The development of trastuzumab was a major triumph of transnational research into finding targeted therapy for cancer. Consequently, once this new drug proved its efficacy in the metastatic setting, it followed that researchers tried to include it in adjuvant regimens. However, to overcome its unexpected cardiac toxicity, new chemotherapy combinations and trial designs had to be sought.

Preclinical and clinical data have indicated dramatic synergistic interactions, with platinum salts and docetaxel forming the basis for an ongoing trial comparing sequential AC and docetaxel with or without trastuzumab to cisplatin or carboplatin with docetaxel and trastuzumab (Breast Cancer International Research Group 006).

Two other trials are examining the efficacy of 4 cycles of AC followed by paclitaxel in different schedules with or without trastuzumab (NSABP B-31, North Central Cancer Treatment Group 9831). Vaccine trials are another type of trial targeting HER2/neu in the adjuvant setting. The theory that maximum efficacy of cancer vaccines is more likely to occur in minimal residual disease than in bulky disease is now accepted.

The success of bisphosphonates in reducing skeletal complications in persons with metastatic breast cancer has suggested a possible role for these noncytotoxic agents in the adjuvant setting. Previous trials have also shown a possible reduction of recurrences in sites other than bone and a survival benefit. To test the potential of this therapy in the adjuvant setting, 3 trials are underway (NSABP B-34, Southwest Oncology Group S9905, CLB-79809).

Postmastectomy Radiotherapy

The 2000 National Institutes of Health Consensus Conference has recognized the benefit of postmastectomy RT in patients with breast cancer who have 4 or more positive lymph nodes, but participants could not make final recommendations for patients with 1-3 positive lymph nodes. Some benefit is probably derived in patients with 1-3 positive lymph nodes; however, because the absolute risk of failure is small, the demonstration of small absolute benefit requires a large clinical trial.

To lift the uncertainty surrounding this issue, the Southwest Oncology Group S9927 trial proposes to assess postmastectomy RT in women with stage II breast cancer with 1-3 positive lymph nodes. The impact of irradiating internal mammary and medial supraclavicular lymph nodes on survival, disease-free survival, metastasis-free survival, and cause of death in women with resected stage I/II/III breast cancer is being evaluated by European Organization for Research and Treatment of Cancer trial 10925. Another European study will compare complete ALND to axillary irradiation in SLN-positive women with operable invasive breast cancer (European Organization for Research and Treatment of Cancer 10981).

Therapy Duration

Optimal duration of different breast cancer therapies is still the subject of discussion. The currently accepted theory is that in the adjuvant setting, 6 months of chemotherapy is equivalent to longer durations. However, controversy remains as to whether 4 months of chemotherapy (AC for 4 cycles) is equivalent to 6 months and, in the event that a longer regimen is used, whether a non–cross-resistant regimen should be implemented.

Adjuvant tamoxifen therapy for 5 years is superior to shorter durations, but whether longer durations are beneficial or detrimental remains to be determined. With the advent of aromatase inhibitors to the adjuvant arena, the question of their optimal duration will fuel the debate for the coming years.

Because of the absence of serious adverse effects, many oncologists tend to use trastuzumab in patients with metastatic breast cancer until progression. To date, whether the continuation of trastuzumab with a different cytotoxic agent is of any benefit to patients whose disease progresses while on combination therapy with trastuzumab and another cytotoxic agent remains unknown. The optimal duration of trastuzumab in the adjuvant setting has not yet been defined and will depend on knowledge gained regarding its mechanism of action. If trastuzumab is mainly a cytostatic drug, its prolonged use is justified; however, if it is found to be cytotoxic, a limited duration may be reasonable.

HER/neu as A Predictor or Prognostic Factor

The role of tissue HER2/neu as a prognostic and predictive factor has not been resolved. Early reports on the prognostic significance of tissue HER2/neu levels based on human and animal research have suggested that HER2/neu overexpression is a poor prognostic factor, although later clinical studies could not confirm these results. Similarly, the role of HER2/neu as a predictive indicator of response to chemotherapy or HT was tempered by the retrospective nature of these studies.

A part of this discrepancy is also related to the lack of a validated measurement assay. Several large retrospective studies analyzing serum banks from HT trials have suggested that elevated serum ECD-HER2 levels are correlated with a poor prognosis and resistance to HT.

Other smaller retrospective studies found similar results regarding serum ECD-HER2, ie, a negative prognostic but not predictive role. Owing to its simplicity and the possibility to express the results quantitatively, serum ECD-HER2 measurements should be included in future prospective trials to determine their exact value.

Patient Selection

Controversy remains regarding the test of choice to select patients who may benefit from trastuzumab. Because this is a targeted therapy, reliably identifying patients who carry the overexpressed target, HER2/neu, is important. Early trials have used IHC, which is a semiquantitative method with high rates of false-positive and false-negative results compared with the more precise method, ie, detection of gene amplification by FISH.

Retrospective analysis of the FISH status of patients with metastatic breast cancer treated with trastuzumab as first-, second-, or third-line therapy showed that FISH was by far superior to IHC in predicting response to this agent. Response to therapy in patients with FISH-negative tumors was close to zero, while all the patients who experienced a clinical response had FISH-positive tumors.

The problem with FISH testing is the need for expensive equipment and consequent limited availability in pathology laboratories. To mitigate these deficiencies, effort was directed toward quantitation of the shedding of HER2/neu in the serum. Although a good correlation exists between serum HER2 levels and HER2/neu expression in the tumor, this test, critics argue, does not accurately reflect the HER2/neu tumor status and cannot register single-cell expression, both required for clinical decision-making processes. The Breast Cancer International Research Group 006 trial is comparing peripheral levels of shed HER2 with FISH for predicting outcome, while the North Central Cancer Treatment Group N9831 trial is examining whether pretreatment levels of shed HER2 and HER1 and their autoantibodies are prognostic.