Bethesda Handbook of Clinical Oncology, 2nd Edition
Hamid R. Mirshahidi
Section of Hematology/Oncology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia
Section of Hematology/Oncology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia
Breast cancer is the most common cancer diagnosed in women in North America, and it is second only to lung cancer as a cause of death from cancer in women. When diagnosed early, breast cancer can be treated primarily using surgery, radiation, and systemic therapy (chemotherapy or hormonal therapy). At the time of diagnosis, more than 90% of patients will have only localized disease.
- In the United States, an estimated 211,240 new cases of invasive breast cancer were diagnosed in women in 2005.
- It had been estimated that in 2005 approximately 40,410 new cases of noninvasive breast cancer [ductal carcinoma in situ(DCIS)] would be diagnosed in the United States.
- In 2004, 40,110 women were expected to die from breast cancer in the United States.
- Approximately 1,450 cases of breast cancer had been estimated to be diagnosed in men in 2004.
- Lifetime risk of developing breast cancer in North American women (who live up to the age of 85) is one in eight.
- The incidence of breast cancer increases with age, but the rate of increase in incidence slows after menopause.
- The 5-year survival rate of all patients with breast cancer is 87.5%.
The risk factors for developing breast cancer in women are listed in Table 12.1.
TABLE 12.1. Risk Factors for Breast Cancer in Women
- Approximately 5% to 10% of all women with breast cancer may have a germ-line mutation of the genes BRCA1or BRCA2.
- Mutations of BRCA1(chromosome 17q21) and BRCA2 (chromosome 13q12–13q13) are responsible for 90% of hereditary breast cancer.
- Specific mutations of BRCA1and BRCA2 are more common in women of Ashkenazi Jewish ancestry.
- The estimated lifetime risk for developing breast cancer in women with a BRCA1or BRCA2 mutation is 40% to 85%, and the risk for developing bilateral breast cancer is 20% to 40%.
- Mutations in either gene also confer a 20% to 40% increased lifetime risk for developing ovarian cancer.
Indications for Genetic Testing
The indications for genetic testing for breast cancer and ovarian cancer are as follows:
- Two or more family members with breast and/or ovarian cancer at age less than 50 years
- Breast cancer and or ovarian cancer at a very young age
- Known BRCA1or BRCA2 mutations in a family member
- Same patient being diagnosed with both breast cancer and ovarian cancer
- One or more family members younger than 50 years with breast cancer and having Ashkenazi Jewish ancestry
- Patients with ovarian cancer having an Ashkenazi Jewish ancestry.
Genetic testing is available commercially (Myriad Genetics). All patients should undergo genetic counseling before the test.
If the test is positive patients have many options including:
- Intense screening using mammogram or magnetic resonance imaging (MRI)
- Chemoprevention using tamoxifen may be considered
- Bilateral prophylactic mastectomy, which could prevent breast cancer in 90% to 100%
- Prophylactic oophorectomy alone reduces breast cancer by 50%.
Eighty percent of breast cancers are invasive ductal carcinoma. Pathologic classification of breast cancer includes:
- Carcinoma, NOS (not otherwise specified)
- Intraductal (DCIS)
- Invasive with predominant intraductal component
- Invasive, NOS
- Medullary with lymphocytic infiltrate
- Mucinous (colloid)
- In situ
- Invasive with predominant in situcomponent
- Paget disease, NOS
- Paget disease with intraductal carcinoma
- Paget disease with invasive ductal carcinoma
- Undifferentiated carcinoma.
The following tumor subtypes occur in the breast but are not considered to be typical breast cancers:
- Cystosarcoma phyllodes
- Primary lymphoma.
The following high-risk lesions are known to occur in breast cancer:
- Atypical ductal hyperplasia (ADH)
- Lobular carcinoma in situ(LCIS) or lobular neoplasia.
- National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study showed a 49% reduction in the incidence of invasive breast cancer in high-risk subjects who took tamoxifen at a dose of 20 mg daily for 5 years.
- Women eligible for this trial were at least 35 years old and were assessed to have an absolute risk of at least 1.67% over the period of 5 years using Gail Model or a pathologic diagnosis of LCIS.
- Gail model is a statistical model that calculates a woman's absolute risk of developing breast cancer by using the following criteria: age, age at menarche, age at first live birth, number of previous biopsies, history of ADH, and number of first-degree relatives with breast cancer. For a free computer disk of this model, call 1-800-4-CANCER or visit the National Cancer Institute (NCI) website (http://www.nci.nih.gov).
- The reduction in the incidence of breast cancer following treatment with tamoxifen is associated with an increase in endometrial cancer (risk ratio of 2.53) and thrombotic events (e.g., pulmonary embolism, with a risk ratio of 3.01) in patients who are older than 50 years.
- Use of tamoxifen for breast cancer should be individualized, and must be considered after weighing the risk–benefit ratio for each patient.
The NSABP P-2 Study of Tamoxifen and Raloxifene (STAR), in which tamoxifen is being compared with raloxifene in postmenopausal women for prevention of breast cancer, has recently completed accrual of patients.
Aromatase inhibitors are being investigated for breast cancer prevention.
- Regular mammographic screening results in early diagnosis of breast cancer and a 25% to 30% decrease in mortality in women older than 50 years.
- A 17% reduction in mortality is seen in women between 40 and 49 years.
- The NCI recommends annual mammography for women aged 40 years and older.
Magnetic Resonance Imaging of the Breast
- MRI is found to be superior to mammogram and ultrasound in young women at high risk for breast cancer and/or in women with BRCA1or BRCA2mutations.
SCREENING FOR HIGH-RISK FAMILY
Women with families at high risk for breast cancer, especially with BRCA1 and BRCA2 mutations, are often advised to undergo mammographic screening from the age of 25, or 5 years earlier than the earliest age at which another family member was diagnosed with breast cancer.
Clinical features could include a breast lump, skin thickening or alteration, peau d'orange, dimpling of the skin, nipple inversion or crusting (Paget disease), unilateral nipple discharge, and so on. Patients could instead present with signs and symptoms of metastatic disease.
The diagnosis of breast cancer includes the following:
- History and physical examination.
- Bilateral mammogram (80% to 90% accuracy).
- Biopsy: Any distinct mass should be considered for a biopsy, even if the mammograms are negative.
The standard methods of diagnosis are:
- Fine-needle aspiration
- Core-needle biopsy
- Incisional or excisional biopsy.
The options in nonpalpable breast lesions are:
- Ultrasound-guided core-needle biopsy
- Stereotactic core-needle biopsy under mammographic localization
- Needle localization under mammography, followed by surgical excision
- MRI-guided biopsy.
- Laboratory studies:
- Complete blood count, liver function tests, and alkaline phosphatase level
- Routine use of breast cancer markers such as CA 27:29 or 15:3 are not recommended but are used widely.
- Pathology review to determine:
- Histology and diagnosis (invasive versus in situ)
- Pathologic grade of the tumor
- Tumor involvement of the margin
- Special studies—estrogen receptor/progesterone receptor (ER/PR) status, HER2/neu status, and indices of proliferation (e.g., mitotic index, Ki-67, or S phase)
- HER2/neu status is studied by immunohistochemistry (IHC) and a result of 3+ is considered positive
- If the IHC result is 2+ (indeterminate), fluorescent in situhybridization (FISH) should be performed for gene amplification.
- Radiographic studies are performed on the basis of the findings of the history and physical examination and screening blood tests:
- Computerized tomography (CT) scan of the chest and abdomen
- Imaging of the brain with CT or MRI
- Bone scan
- Chest radiograph.
STAGING OF BREAST CANCER
The American Joint Committee on Cancer (AJCC) staging of breast cancer and the pathologic classification are listed in Tables 12.2, 12.3, and 12.4.
TABLE 12.2. Staging of Breast Cancer (American Joint Committee on Cancer)
TABLE 12.3. Pathologic Classification (pN)
TABLE 12.4. American Joint Committee on Cancer Stage Groupings
- Number of positive axillary lymph nodes
- This is one of the most powerful prognostic indicators.
- Tumor size
- Tumors smaller than 1 cm have a good prognosis in patients without lymph node involvement.
- Histologic or nuclear grade
- Patients with poorly differentiated histology and high nuclear grade have a worse prognosis than others.
- Scarff–Bloom–Richardson (SBR) grading system and Fisher nuclear grade are commonly used systems.
- ER/PR status
- ER- and or PR-positive tumor has better prognosis.
- Histologic tumor type
- Prognoses of infiltrating ductal and lobular carcinoma are similar.
- Mucinous (colloid) and typical medullary and tubular histologies have good prognosis if the size is <3 cm.
- Inflammatory breast cancer has poor prognosis.
- HER2/neu overexpression is clearly associated with poor prognosis.
- Median survival of patients with tumors exhibiting HER2/neu overexpression is 3 years compared to HER2/neu–negative patients who have a median survival of 6 to 7 years.
- Gene Expression Profiles
- Oncotype DX is a new diagnostic genomic assay based on an NSABP study. This assay can accurately and precisely quantify the likelihood of cancer recurrence in women with newly diagnosed, stage I or II, node-negative, ER-positive breast cancer. Patients are divided into low-risk, intermediate-risk, and high-risk groups on the basis of the expression of a panel of 21 genes. The recurrence score determined by this assay is found to be a better predictor of outcome than standard measures such as age, tumor size, and tumor grade.
MANAGEMENT OF BREAST CANCER
Patients with high-risk lesions may be eligible for breast cancer prevention studies.
Atypical Ductal Hyperplasia
- There is a fourfold to fivefold increase in the risk of developing breast cancer in patients with ADH.
- There is wide variation in the criteria used in the diagnosis of ADH.
- ADH is managed by close follow-up of patients.
- Clinical breast examination and mammogram are the preferred screening methods.
- Tamoxifen 20 mg PO for 5 years: NSABP P-1 study showed 86% reduction in the risk for developing invasive breast cancer in patients who received tamoxifen.
Lobular Carcinoma In Situ
- LCIS is not considered a form of cancer but a marker of increased risk for developing invasive breast cancer.
- It is usually multicentric and bilateral.
- There is a 21% chance of developing breast cancer in patients within 15 years of developing LCIS.
- It is managed by close follow-up of patients.
- Clinical breast examination every 4 to 12 months and annual mammogram is essential.
- Tamoxifen may be used for prevention of breast cancer (56% reduction in risk as per the NSABP P-1 study).
Noninvasive Breast Cancer
Ductal Carcinoma In Situ
- With the extensive use of mammograms, the diagnosis of DCIS has increased over the last few years.
- Microcalcification or soft-tissue abnormality is seen in the mammogram in cases of DCIS.
Different Histologic Types of Ductal Carcinoma In Situ
- Comedocarcinoma has a poor prognosis.
- Non–comedocarcinoma includes micropapillary, papillary, solid, and cribriform carcinoma.
- Lumpectomy followed by radiation treatment plus tamoxifen is the standard treatment option.
- Other treatment options are:
- Total mastectomy with or without tamoxifen
- Breast-conserving surgery without radiation therapy, which could be considered in select patients with low Van Nuys Prognostic Index (VNPI), which combines four predictors of local recurrence (tumor size, margin width, pathologic classification, and age).
- In patients who previously had lumpectomy and radiation, tamoxifen reduced the risk of breast cancer recurrence (ipsilateral and contralateral; NSABP B-24). Recent subset analysis of B-24 showed that the benefit was more obvious in patients with ER/PR-positive DCIS.
- The role of aromatase inhibitors such as anastrozole is being investigated for receptor-positive DCIS in a large NSABP (B-35) study.
Invasive Breast Cancer
Early stage Breast Cancer
No survival difference is seen in patients who are treated with modified radical mastectomy versus those treated with lumpectomy plus radiation. Breast preservation with lumpectomy plus radiation therapy is the preferred treatment for breast cancer.
Contraindications for Lumpectomy:
- Two or more tumors in separate quadrants of the breast
- Diffuse, indeterminate, or malignant-appearing microcalcifications
- Central location of the tumor mass.
Contraindications for Radiation:
- History of therapeutic irradiation to the breast
- Connective tissue disorders (scleroderma)
Axillary Lymph Node Dissection:
- Axillary lymph node dissection (ALND) primarily provides prognostic information. It has minimal therapeutic benefit, especially in clinically negative axillae.
- Histologically positive axillary lymph nodes are the most important prognostic factor.
- Among patients with clinically negative axillary lymph nodes, 30% will have positive histology after dissection.
- It is associated with approximately 10% to 25% risk of lymphedema, which can be mild to severe. This varies with the level of axillary node dissection.
Sentinel Node Biopsy:
- Sentinel node biopsy (SNB) is a minimally invasive procedure for axillary staging.
- A radioactive substance or blue dye is injected into the area around the tumor.
- The ipsilateral axilla is explored and the node that has taken up the dye or radioactive material is excised and examined pathologically.
- In expert hands, this procedure identifies a node in more than 92% to 98% of patients.
- Reconstructive surgery may be used for patients who opt for a total mastectomy. It may be done at the time of the mastectomy (immediate reconstruction) or it can be delayed.
- Radiotherapy (RT) is an integral part of breast-conserving treatment (lumpectomy).
- Radiation boost up to 4,500 to 5,000 cGy ± 1,000 to 1,500 cGy to the tumor bed of the breast is effective.
- In patients who need chemotherapy, RT is usually done after chemotherapy.
- Postmastectomy radiation treatment to the chest wall and supraclavicular lymph nodes decreases the risk of locoregional recurrence in patients with four or more positive lymph nodes and in patients with tumor size >5 cm.
- Two randomized trials showed improvement in overall survival (OS) for postmastectomy radiation in patients with one to three positive lymph nodes, and it is being evaluated in more clinical trials.
Newer Radiation Techniques under Investigation:
- Partial breast irradiation (PBI)is under investigation and may be used in clinical trial at this point.
- Partial breast brachytherapy (PBB)or interstitial brachytherapy is also undergoing clinical trials in stage I and II patients with free resected margins and zero to three positive lymph nodes. In the PBB method, patients receive ten fractions of radiations of 3.4 Gy within 5 days.
- Mammosite Radiation Therapy System (RTS)was approved by the U.S. Food and Drug Administration (FDA) on May 6, 2002, for patients with T2 N0 M0 breast cancer. Radiation of 34-Gy is delivered in ten fractions within 5 days through a balloon inserted at the lumpectomy site during surgery.
Systemic Treatment for Early Breast Cancer
Chemotherapy is recommended for most of the patients with node-positive disease. For node-negative patients, the treatment is based on many factors, such as the tumor size, ER/PR status, nuclear or histologic grade (Table 12.5).
TABLE 12.5. Risk Categories for Patients with Node-negative Breast Cancer
Multiple systemic chemotherapy regimens are used including AC (doxorubicin and cyclophosphamide), CMF [cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU)], AC followed by a taxane, EC, CAF (cyclophosphamide, doxorubicin, 5-FU), CEF (cyclophosphamide, epirubicin, 5-FU), FAC (5-FU, doxorubicin, and cytoxan), TAC (taxotere, adriamycin, and cytoxan).
- CALGB 9344 and NSABP B-28 trials showed that adding four cycles of paclitaxel to four cycles of AC improves the disease-free survival (DFS) and OS in node-positive patients.
- CALGB 9741 trial showed that dose-dense chemotherapy in which node-positive patients received the same total doses of AC followed by paclitaxel on a 2-week regimen rather than a 3-week schedule with growth factor support had a superior DFS and OS.
- BCIRG 001 trial showed improvement in DFS and OS in node-positive early stage breast cancer patients who were treated with TAC versus the standard FAC regimen (see Table 12.6 and Fig. 12.1).
FIG. 12.1. Treatment algorithm for early breast cancer.
- LR = Low Risk, IR = Intermediate Risk, HR = High Risk, Chemotheraphy = Cx, Tamoxifen = Ta, Aromatase inhibitor = Al, GnRH Analog = GA Ovarian Ablation = OA
- Treatment in older women should be individualized.
*This treatment option is under clinical evaluation.
- Adapted from NCI PDQ.
TABLE 12.6. Commonly used Combination Chemotherapy Regimens
Antiestrogen therapy in the adjuvant setting:
Antiestrogen therapy is recommended only for ER-positive and/or PR-positive patients.
- Tamoxifen is a selective estrogen-receptor modulator (SERM).
- In early stage breast cancer, tamoxifen decreases the risk of recurrence by 42% and the absolute risk of death by 22% in both pre- and postmenopausal women with ER-positive tumors.
- Tamoxifen decreases the incidence of breast cancer in the contralateral breast by approximately 50%.
- Recommended treatment is tamoxifen, 20 mg per day PO for 5 years.
- Anastrozole is an aromatase enzyme inhibitor approved for adjuvant treatment of postmenopausal women.
- Arimidex, Tamoxifen, Alone or in Combination(ATAC) trial showed that anastrozole has a favorable side-effect profile (especially thromboembolic disease and endometrial cancer) and superiority over tamoxifen in contralateral breast cancer reduction, DFS, and OS.
- The dose of anastrozole is 1 mg PO everyday for 5 years.
- Major side effects include joint pain and osteopenia, osteoporosis, and fracture.
A recent study showed approximately 43% reduction in recurrence in patients receiving 2.5 mg of letrozole after completing 5 years of tamoxifen (extended adjuvant therapy) (1).
Exemestane therapy after 2 to 3 years of tamoxifen therapy significantly improved DFS and reduced the incidence of contralateral breast cancer as compared with the standard 5 years of tamoxifen therapy (2). A smaller but similar study from an Italian group showed an improvement in DFS by switching to anastrozole after 2 to 3 years of tamoxifen.
Locally Advanced Breast Cancer and Inflammatory Breast Cancer
Locally advanced breast cancer and inflammatory breast cancer have the following features:
- Tumor ≥5 cm
- Tumors of any size, with direct invasion of the skin of the breast or chest wall (T4)
- Any tumor with fixed or matted axillary lymphadenopathy (N2).
- Initial surgery is limited to biopsy to confirm the diagnosis and to identify the receptor status.
- Neoadjuvant (primary) chemotherapy: NSABP B-18 (AC for four cycles) and B-27 (AC followed by Taxotere for four cycles) showed a higher clinical and pathologic response rate in patients who received neoadjuvant chemotherapy.
- Surgery is performed after the best response to preoperative chemotherapy.
- Radiation therapy to the chest wall and supraclavicular area is performed after surgery.
Metastatic Breast Cancer
- The treatment goal is to palliate symptoms and to improve survival.
- All patients should be considered for ongoing clinical trials.
- In 5% to 15% of patients, durable complete remission can be achieved with systemic therapy.
- Local control may be achieved by surgery and/or radiation treatment.
- In hormone receptor–positive patients with soft-tissue, bone, or asymptomatic visceral disease, hormonal agents should be considered as the first-line therapy (see Table 12.7).
- Chemotherapy regimens can be used as the initial treatment in hormone receptor–negative disease or in patients with symptomatic visceral disease.
- Quality of life should be an important consideration.
- Most of the patients could be treated with sequential single agents, but in select patients, combination chemotherapy also could be used (see Fig. 12.2).
FIG. 12.2. Algorithm for the management of metastatic breast cancer (3). (From Hortobagyi GN. Treatment of breast cancer. N Engl J Med 1998;339:974–984.).
TABLE 12.7. Hormonal Agents used in Metastatic Breast Cancer
- Bisphosphonates should be used in patients with bony metastatic disease because they prevent progression of lytic lesions, delay skeletal-related events, and decrease pain.
- Zoledronic acid (4 mg by 15-minute infusion) and pamidronate (90 mg by 2-hour infusion) are two available biphosphonates approved for bony metastatic disease.
Commonly Used Chemotherapy Agents in Metastatic Breast Cancer:
- Liposomal doxorubicin
- Alkylating agents
- Vinca alkaloids
- Trastuzumab (Herceptin) is a humanized monoclonal antibody that binds to the HER2/neu receptor.
- It is indicated in patients with metastatic disease whose tumor overexpresses HER2/neu protein (3 + by IHC or FISH positive).
- Approximately 25% of the patients overexpress HER2/neu.
- Herceptin is combined with many chemotherapy agents including docetaxel, paclitaxel, navelbine, gemcitabine, and carboplatin.
- Initial dosage is trastuzumab, 4 mg per kg i.v. over 90 minutes, followed at weekly intervals by maintenance with trastuzumab, 2 mg per kg i.v. over 30 minutes if the initial infusion rate is well tolerated.
- Pharmacokinetic studies show that Herceptin could be given every 3 weeks (8 mg per kg loading dose and 6 mg per kg every 3 weeks), and many clinical trials are ongoing to test this regimen.
- Preexisting cardiac disease and cardiomyopathies associated with prior treatments (e.g., anthracycline drugs and radiation to the chest) may be exacerbated by trastuzumab.
- The probability of cardiac dysfunction is greatest in patients who receive the therapy concurrent with anthracycline drugs (e.g., doxorubicin).
It is an oral antimetabolite that is anabolized to 5-FU in tumors. It is the third-line therapy for metastatic breast cancer after anthracyclines and taxanes or second-line therapy if anthracyclines are not indicated. FDA-approved dosage is 1,250 mg per m2 PO BID for weeks followed by 1 week rest and given every 3 weeks. Lower doses such as 900 to 1,000 mg per m2 PO BID is widely used. Major side effect is hand–foot syndrome.
Abraxane is an albumin-stabilized nanoparticle formulation of paclitaxel. It eliminates the need for toxic solvents like cremophor and steroid pretreatment. FDA approved ABRAXANE.
- Oophorectomy can be considered in premenopausal patients.
- It can be done with surgical, radiation, or chemical methods.
Recurrent Breast Cancer
- After mastectomy:
- Eighty percent of local recurrences occur within 5 years.
- The treatment of choice is surgical excision and RT.
- Systemic therapy may be considered, although the survival advantage is not clear.
- After lumpectomy:
- Mastectomy is the treatment of choice for patients who have only isolated breast cancer recurrence.
- The 5-year relapse-free survival is 60% to 75%, if treated only with mastectomy.
Breast Cancer in Pregnancy
- Breast cancer diagnosis may be delayed in pregnant women.
- Breast cancer during pregnancy was thought to be more aggressive, but the overall poor outcome is likely related to advanced stage at the time of diagnosis.
- Breast biopsy is safe in all stages of pregnancy and should be done for any suggestive mass.
- Lumpectomy and axillary dissection can be performed in the third trimester, and RT can be safely delayed until after delivery.
- Modified radical mastectomy is the treatment of choice in the first and second trimesters because radiation treatment is contraindicated during pregnancy.
- Chemotherapy should not be administered during the first trimester.
- No chemotherapeutic agent has been found to be completely safe during pregnancy.
- An anthracycline combined with cyclophosphamide (e.g., AC given every 3 weeks for four cycles) has been used in the adjuvant setting during the second or third trimesters.
- Chemotherapy should be scheduled to avoid neutropenia and thrombocytopenia at the time of delivery.
- Paclitaxel is teratogenic and should not be used during pregnancy.
- Tamoxifen is teratogenic and should not be used in pregnant women.
- Therapeutic abortion does not change the survival rate.
Male Breast Cancer
- Male breast cancer is uncommon.
- Risk factors are family history, BRCA2germ-line mutation, Klinefelter syndrome, and radiation.
- Presence of gynecomastia is not a risk factor for breast cancer.
- It is first seen as a mass beneath the nipple or ulceration.
- The mean age of occurrence is 60 to 70 years.
- Eighty percent of male breast cancer is hormone-receptor positive.
- Modified radical mastectomy.
- Lumpectomy is rarely done because it does not offer any cosmetic benefit.
- Systemic treatment with chemotherapy and antiestrogen should follow the general guidelines for female patients.
- None of the adjuvant treatment modalities has been tested in a randomized clinical trial setting in men.
FOLLOW-UP FOR PATIENTS WITH OPERABLE BREAST CANCER
- History and physical examination every 3 to 6 months for the first 3 years, every 6 to 12 months for the next 2 years, and then annually.
- Monthly breast self-examination.
- Annual mammogram of the contralateral and ipsilateral (remaining breast after lumpectomy) breast.
- Annual Papanicolaou smear and pelvic examinations in women who are taking, or who have taken, tamoxifen.
- Complete blood count, liver function tests, and alkaline phosphatase levels obtained with physical examination.
- Serum tumor markers (CA 27, 29, and CA 15-3) are not recommended.
- Bone scan and imaging of the chest, abdomen, pelvis, and brain are not recommended routinely, but they are done if symptoms or laboratory abnormalities are present.
- Rectal examination, occult blood testing, and skin examination must be performed annually or every 2 years.
- (From recommendations by American Society of Clinical Oncology, with permission.)
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