MANAGEMENT OF BREAST CANCER
Selections from General Surgery 2005 — 27th Annual Postgraduate Course, presented by the University of California, Davis,
Health System
| CURRENT STATUS OF SENTINEL LYMPH NODE BIOPSY —Kelly K. Hunt, MD, Professor and Chief, Surgical
Breast Section, Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston
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| Sentinel lymph node biopsy (SNLB) technique: McMasters et al—100 surgeons submitted information on mapping
procedure in 806 patients; all patients received SLNB followed by axillary lymph node dissection (ALND); single-
agent (blue dye or radioisotope) injection used in 244 patients, dual-agent injection used in 562 patients; more sentinel
lymph nodes (SLNs) identified (not statistically significant) and false-negative rate significantly lower with dual agent
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| American Society of Breast Surgeons consensus statement: individual surgeon should perform at least 20
cases of SLN surgery with ALND and analyze false-negative and identification rates before abandoning ALND; acceptable
false-negative rate 5%
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| Pathologic evaluation: MD Anderson approach—section SLN along short axis (try to get 2-4 mm sections; if node
fatty, more difficult to get thin sections); embed sections in paraffin; from each block, perform hematoxylin and eosin
(H&E) staining on 2 sections and cytokeratin immunohistochemistry on 1 section; technique identifies macrometastases
and most micrometastases in 98% of patients
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| National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32: patients with clinically negative axillary
nodes stratified by age, clinical tumor size, and surgery type (mastectomy and breast conservation); patients randomized
to SLND followed by ALND or SLND alone (ALND performed if SLN histologically positive); technical success rate
97.2% for SLND plus ALND, 97% for SLND alone; average number of SLN recovered 2.9; overall false-negative rate
9.7%; technical success good for all T stages, although slightly lower (statistically significant) for T3 tumors; false-negative
rate similar for all T stages (highest for T1)
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| American College of Surgeons Oncology Group Z00010 trial: patients with clinical T1 or T2 breast cancer
scheduled to undergo breast conservation received SLND and bilateral bone marrow aspiration; patients with negative
SLN followed but did not receive specific axillary treatment; only patients with histologically positive SLN received
ALND
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 | Surgical outcomes (Wilke et al, 2005): 5327 eligible patients; median age 56 yr; histologically positive SLN rate 24%;
short-term surgical effects consisted of allergic reactions, wound infections, and axillary paresthesias; long-term surgical
effects consisted of axillary paresthesias and lymphedema; 30-day outcomes—clinically evident seroma formation
7.1%; small incidence of hematoma or infection; 6-mo outcomes—lymphedema (based on arm circumference) 7%;
decreased range of motion 3.8%; paresthesias 9%; lymphedema—defined as increase in arm circumference of 2 cm;
older age and high body mass index (BMI) only clinical predictors
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| Technical results (Giuliano et al, 2005): overall, SLN identification rate 98.7%; mean number of SLN recovered 2.26
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| Predictors of SLND failure: surgeon factors—surgeons who enrolled <50 patients in Z00010 trial; patient factors—older
age and high BMI
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| Axillary recurrence (median follow-up 31 mo): recurrence 0.3% for patients with positive or negative SLN; median time
to recurrence 19 mo
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| Anaphylactic reactions: study—allergic reactions (eg, development of blue hives) and significant anaphylactic events
seen; of first 639 patients who underwent mapping with blue dye, anaphylaxis rate 1.1%; preoperative protocol—
prophylaxis with steroids and diphenhydramine (Benadryl) prevented anaphylactic events but did cause other side effects
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| Evolving controversies (SLND vs ALND): significance of micrometastases unclear; SLND has improved axillary
staging, but presence of single positive cells can confuse issue (speaker recommends using modified American Joint
Committee on Cancer [AJCC] staging system and that patients with single positive cells be classified as node-negative);
local–regional control appears to be maintained with SLND; morbidity higher than expected with SLND
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| Completion ALND: American Society of Clinical Oncology (ASCO) guidelines recommend completion ALND for all
patients with positive SLN; nomogram—available at www.mskcc.org/mskcc/html/15938.cfm; calculates risk of having
additional axillary metastases when SLN positive; National Comprehensive Cancer Network guidelines—recommend
ALND when SLN positive or no SLN identified
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| IS MRI READY FOR PRIME TIME ?—Richard J. Bold, MD, Associate Professor, Division of Surgical Oncology, University
of California, Davis, School of Medicine
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Screening
| Study: >200 asymptomatic Canadian women with known BRCA1 or BRCA2 mutations underwent screening with clinical
breast examination (CBE), mammography, ultrasonography (US), and magnetic resonance imaging (MRI); average follow-up
2 yr; of 22 cancers identified (16 invasive, 6 in situ), 13 identified at initial evaluation, 7 at 2 yr, and 2 at 3 yr; of
16 invasive cancers, 13 detected by MRI (only 1 detected by CBE); of 6 in situ cancers, 4 detected by MRI; mammography
and CBE missed 3 in situ cancers, measuring 3, 4, and 6 cm; 2 cancers missed by MRI represented very small cancers;
MRI had highest sensitivity; in first year, 15 patients (7%) had biopsy for MRI abnormality that was subsequently
benign
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| Rotterdam Family Cancer Clinic: high-risk patients (due to BRCA1 or BRCA2 mutation or family history) received
CBE, mammography, and MRI; 51 tumors identified; MRI had higher sensitivity than other screening modalities
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| Conclusion: for high-risk patients, MRI may be useful for screening in absence of other abnormalities
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Diagnosis
| Study: >800 women had MRI performed before biopsy for suspicious mammogram; for 400 cancers, MRI sensitivity
90%; for 400 benign lesions, 136 had MRI that showed abnormal lesion that warranted biopsy (low specificity);
conclusion—MRI not second step for patient with abnormal mammogram sufficient to warrant biopsy
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| Study: 86 patients with Breast Imaging Reporting and Data System (BI-RADS) 3 (indeterminate abnormality) mammograms
had MRI, 50% had US; 36 patients had suspicious MRI findings, of which 26 biopsied, revealing 10 cancers; of 48
patients with benign MRIs, none developed cancer; conclusion—for patients with BI-RADS 3 mammograms, MRI helpful
with management; MRI vs US—47 patients had US; of 6 suspicious US scans, 0 cancers detected on biopsy; of 41 benign
US scans, 4 cancers developed
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Staging
| Study: 170 patients with diagnosed breast cancer had MRI, mammography, and US to evaluate extent of cancer; for patients
with multifocal cancer, MRI had highest sensitivity; MRI documented 21 of 22 patients with multicentric cancers
and all 9 patients with bilateral cancers; predictors of additional findings on MRI included dense breast, larger lesion, extensive
in situ cancer (EIC), or large ductal carcinoma in situ (DCIS)
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| Occult cancer: study—of 22 patients with axillary metastases in whom primary breast cancer could not be identified, 19
had breast cancer identified by MRI (median size 17 mm)
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| Infiltrating lobular carcinoma (ILC): “mammogram truly underestimates extent of tumor”; study—34 patients with
ILC evaluated with mammography, US, and MRI preoperatively; MRI only modality to give accurate evaluation of true extent
of cancer
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| HORMONE REPLACEMENT THERAPY AND CANCER RISK —James E. Goodnight, Jr, MD, PhD, Professor and Pearl
Stamps Stewart Chair, Department of Surgery, University of California, Davis, School of Medicine
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| Combined estrogen and progestin: Women’s Health Initiative data—breast cancer risk increased 25% with use of
combined estrogen and progestin; however, risk reduced for endometrial cancer and colon cancer (risk reduction 35%);
breast cancer risk increases with length of use
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| Unopposed estrogen: increases breast cancer risk, but not as much as with combined therapy; increases risk for endometrial
cancer; recent study shows prolonged use over long period doubles ovarian cancer risk
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| Use in patients with or at high risk for breast cancer: withdrawal of estrogen helpful in hormone receptor–positive
patients, suggesting hormone replacement therapy (HRT) contraindicated; treatment of premenopausal patients with
adjuvant chemotherapy and prolonged treatment of postmenopausal patients with aromatase inhibitors leading to increasing
population of breast cancer patients who are estrogen deprived, suggesting HRT contraindicated
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| Women’s Health Initiative: reversed notion that HRT good for all patients; data showed HRT increased risk for breast
cancer and increased risk for cardiovascular disease by 30%; Food and Drug Administration (FDA) has changed labeling to
state HRT should be used for short-term control of vasomotor symptoms
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| Alternative treatments for menopausal symptoms: antidepressants—venlafaxine (Effexor) 75 mg/day effective
(generally, >50% of patients show improvement in symptoms); fluoxetine and paroxetine also effective; 20% of patients
complain of gastrointestinal (GI) distress, tremors, and insomnia, and 30% report some degree of sexual dysfunction;
gabapentin (Neurontin)—300 to 900 mg/day effective; can be used in conjunction with antidepressants; over-the-counter
preparations—black cohosh has not shown good results in clinical trials; soy products likely help but contain phytoestrogens
that can have deleterious effects; evening primrose oil and vitamin E have shown no benefit
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| Treatment and prevention of osteoporosis and osteopenia: bisphosphonates (alendronate [Fosamax]) effective
as antiresorptive agent; smoking cessation; reduce alcohol consumption; adequate intake of vitamin D (600-800 IU/day)
and calcium (1200-1500 mg/day); regular weight-bearing exercise; raloxifene (selective estrogen receptor modulator) effective
antiresorptive agent but causes hot flushes
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| Local estrogen preparations: vaginal estrogen creams—effective for vaginal dryness and urogenital symptoms; systemic
absorption low but enough to alter lipid profile; progestins (megestrol [Megace])—effective for vasomotor symptoms;
however, mitogenic for breast cancer cells in vitro
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| NEOADJUVANT CHEMOTHERAPY AND BREAST CONSERVATION —Dr. Hunt
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| Rates of breast conservation
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| NSABP B-18: patients with operable breast cancer stratified by age, clinical tumor size, and clinical nodal status; patients
randomized to surgery followed by 4 cycles of chemotherapy and tamoxifen if >50 yr of age with estrogen receptor-
positive disease or to chemotherapy first followed by surgery; results—lumpectomy rate 60% for patients who had
surgery first, compared to 68% for patients who had preoperative chemotherapy; Fisher et al—proportion of patients
who gained option of breast conservation increased 8% (60% to 68%); of 40% of patients initially ineligible for breast
conservation, breast conservation possible in 8 patients (20%) following preoperative chemotherapy
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| Ipsilateral breast tumor recurrence (IBTR) after chemotherapy
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| NSABP B-18: over time, IBTR rates increase in both groups but higher in preoperative chemotherapy group (not statistically
significant); no difference in survival between groups; Wolmark et al—in adjuvant group, IBTR rate 7.6%; in
neoadjuvant (preoperative) group, IBTR rate higher in mastectomy candidates downstaged to breast conservation,
compared to those eligible for breast conservation initially
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| MD Anderson Cancer Center experience
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| Standard approach: patients with locally advanced breast cancer received 4 cycles of fluorouracil plus doxorubicin and
cyclophosphamide (FAC); if no response, patients underwent radiation and mastectomy; if objective response, patients
underwent breast conservation or mastectomy, then received adjuvant chemotherapy, and irradiation and tamoxifen as
indicated
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| Monitoring response to chemotherapy: patients underwent baseline and follow-up mammography and US to assess response;
tumor marking—after 1 or 2 cycles of chemotherapy, tumor often disappears; metallic markers (eg, standard
biopsy clips, embolization coils) easy to see on US and mammography and help localize lesions for resection
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| Pathologic and radiographic assessment: specimen (marked for anatomic margins) inked with 6 colors and sectioned; radiographic
assessment performed on most specimens, which can reveal areas of density and calcifications that may
represent residual disease
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| Study population: 357 patients; median age 46 yr (majority premenopausal); many had stage III disease, but others had
operable disease; majority of patients had negative margins, but others had close, positive, or unknown margins
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| IBTR results: overall IBTR-free rate 94% at 5 yr and 90% at 10 yr; predictors of recurrence included lymphovascular space
invasion (LVSI); patients with multifocal pattern of residual disease or residual tumor >2 cm after chemotherapy more
likely to have recurrence; T stage did not affect recurrence; patients with initial large multifocal tumor more likely to have
recurrence than patients with small multifocal tumor
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| MD Anderson prognostic index: presence of advanced nodal disease (N2 or N3), LVSI, tumor >2 cm, and multifocality
scored as yes (0 point) or no (1 point); total score range 0 to 4; of 357 patients studied, prognostic score 0 in large number,
with none scoring 4; patients with prognostic score of 3 had higher rates of local regional recurrence (LRR) and IBTR
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| Nodal stage and LRR: patients with advanced nodal stage had higher rates of LRR, regardless of whether they underwent
breast conservation or mastectomy and irradiation
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Educational Objectives
| The goal of this program is to educate the listener on the management of breast cancer. After hearing and assimilating this
program, the clinician will be better able to:
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| 1. Manage patients with breast cancer.
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| 2. Employ sentinel lymph node biopsy in the evaluation of patients with breast cancer.
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| 3. Discuss the role of magnetic resonance imaging for screening, diagnosis, and staging of breast cancer.
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| 4. Counsel patients with or at high risk for breast cancer on the use of hormone replacement therapy.
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| 5. Review the evidence supporting the safety and efficacy of neoadjuvant chemotherapy and breast-conservation therapy.
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Discussed on This Program
Alendronate sodium [Fosamax]
Cyclophosphamide [Cytoxan, Cytoxan Lyophilized, Neosar]
Diphenhydramine HCl (several trade names)
Doxorubicin [Adriamycin PFS, Adriamycin RDF]
Fluorouracil (5-fluorouracil, 5-FU) [Adrucil, Carac, Efudex, Fluoroplex]
Fluoxetine HCl [Prozac, Prozac Pulvules, Prozac Weekly, Sarafem, Sarafem Pulvules]
Gabapentin [Neurontin]
Megestrol acetate [Megace, Megace ES]
Paroxetine HCl [Paxil, Paxil CR, Pexeva]
Venlafaxine HCl [Effexor, Effexor XR]
Suggested Reading
Albo D et al: Anaphylactic reactions to isosulfan blue dye during sentinel lymph node biopsy for breast cancer. Am J
Surg 182:393, 2001; Bluemke DA et al: Magnetic resonance imaging of the breast prior to biopsy. JAMA 292:2735,
2004; Buchholz TA et al: Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer response to
chemotherapy. Cancer J 9:33, 2003; Chagpar AB et al: Factors predicting failure to identify a sentinel lymph node in
breast cancer. Surgery 138:56, 2005; Chao C, McMasters KM: Sentinel lymph node biopsy in breast cancer. Methods
Mol Med 120:91, 2006; Chen AM et al: Breast conservation after neoadjuvant chemotherapy. Cancer 103:689, 2005;
Chen AM et al: Breast conservation after neoadjuvant chemotherapy: the MD Anderson cancer center experience. J Clin
Oncol 22:2303, 2004; Chlebowski RT et al: Estrogen deficiency symptom management in breast cancer survivors in
the changing context of menopausal hormone therapy. Semin Oncol 30:776, 2003; Gundry KR: The application of breast
MRI in staging and screening for breast cancer. Oncology (Williston Park) 19:159, 2005; Harlow SP et al: Prerandomization
Surgical Training for the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial: a randomized
phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node-negative
breast cancer. Ann Surg 241:48, 2005; Hersh AL et al: National use of postmenopausal hormone therapy: annual trends
and response to recent evidence. JAMA 291:47, 2004; Kriege M et al: Efficacy of MRI and mammography for breast-
cancer screening in women with a familial or genetic predisposition. N Engl J Med 351:427, 2004; Leitch AM et al: Patterns
of participation and successful patient recruitment to American College of Surgeons Oncology Group Z0010, a phase
II trial for patients with early-stage breast cancer. Am J Surg 190:539, 2005; Moorman PG et al: Menopausal hormones
and risk of ovarian cancer. Am J Obstet Gynecol 193:76, 2005; Scoggins CR et al: Should sentinel lymph-node biopsy
be used routinely for staging melanoma and breast cancers? Nat Clin Pract Oncol 2:448, 2005; Warner E et al: Surveillance
of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical
breast examination. JAMA 292:1317, 2004; Wilke LG et al: Surgical complications associated with sentinel lymph node
biopsy: results from a prospective international cooperative group trial. Ann Surg Oncol 13:491, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the speakers reported
no conflict.
Drs. Hunt, Bold, and Goodnight spoke at General Surgery 2005 — 27th Annual Postgraduate Course, presented September
16-17, 2005, by the University of California, Davis, Health System, and held in Napa Valley, CA. The Audio-Digest
Foundation thanks the speakers and the sponsor for their cooperation in the production of this program.
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