TOPICS IN BREAST CANCER
| ULTRASOUND IN BREAST SURGERY PRACTICE— Rache M. Simmons, MD, Associate Professor of Surgery and Director
of Breast Cancer Surgical Research, Joan and Sanford I. Weill Medical College of Cornell University, New York
City
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| Screening: screening ultrasonography (US) can result in many women having biopsies but few cancers being detected;
judgment required on who receives screening US; speaker offers screening US to high-risk women (eg, patients with
strong family history or known breast cancer [BRCA] gene mutation) or young patients with personal breast cancer history;
screening indicated for postmenopausal women taking hormone replacement therapy who have very dense breast
tissue and patients who have had augmentation mammoplasty
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| “Stethoscope of the breast”: US can be used in office setting to differentiate between simple cysts requiring no treatment,
complex cysts and septated lesions requiring precautionary aspiration, solid masses requiring core biopsy or excision, and irregular,
likely cancerous, masses requiring core biopsy; US guidance—can be used for fine-needle aspirations to remove
cysts in 20 min; core biopsy—results can be obtained within 48 hr
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| Intraoperative US localization: more effective way of localizing lesions than radiology; with radiologically localized lesions,
difficult to know where lesion located on wire, unless mammography performed; patients prefer US localization;
performing intraoperative US localizations gives surgeon better control over operating schedule and allows surgeon to insert
wire in preferred manner in accordance with desired location of incision; issues with US localization—elements
not normally visible on US can be made visible to aid localization; hematoma from core biopsy can be used as guide for
lesion excision; can inject patient’s own blood at time of magnetic resonance imaging (MRI)–guided core biopsy to give
hematoma for localization in operating room; GelMark technology by SenoRx involves gel marker, inserted with pledget
during core biopsy, that becomes echogenic by absorbing body’s serous fluid and allows lesion to be seen on US
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| Tumor excision: benign tumors can be almost completely removed using 8- or 11-gauge mammotome-type device and US
localization; in future, technology likely will be used to excise breast cancers; technique—mammotome-type device
uses suction to extract piece of tumor, which gets extruded into collection canister; canister removed and sent to pathology;
process repeated until entire tumor excised; clinical experience—in patients with atypical hyperplasia who underwent
excision and resection, very few had adenomatous hyperplasia or malignancy upon surgical excision; only 1 of 4
patients with cancerous tumors had residual disease
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| BONE MARROW ASPIRATION IN BREAST CANCER —Dr. Simmons
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| Evaluation for systemic disease: sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND)—
30% of patients with negative axillary nodes die of systemic disease, and 40% of patients with positive axillary nodes
survive >10 yr; computed tomography (CT) of lung and liver and bone scans—limitations include inability to see single
cells
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| Bone marrow aspiration: multiple studies show bone marrow micrometastases (BMM) and bone marrow aspiration test
give additional information about likelihood of patient having metastatic disease; commonly used in Europe but controversial
in United States; technique—simple procedure taking 5 min to perform in operating room while patient under sedation;
11-gauge Illinois needle inserted through incision, and 5 mL aspirated from each anterior hip bone; aspirate
placed in green-top tube containing heparin, then sent to pathology for cytospin and pancytokeratin immunohistochemical
stain
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| Bone marrow micrometastases: detected in 27% to 42% of patients with stage I to III breast cancer; of patients with best-
risk criteria (node negative, tumor diameter <1 cm), 10% to 22% BMM positive; Braun et al—probability of being free of
distant metastases after surgery significantly greater for BMM-negative than BMM-positive patients; Cote et al—BMM-
negative patients have 3% likelihood of distant recurrences at 2 yr, compared to 33% for BMM-positive patients; distant metastases
no more likely to appear in bone than other sites, eg, liver or lung; Braun et al—probability of survival after surgery
significantly greater for BMM-negative than BMM-positive patients
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| Literature review: Braun et al—>500 patients followed for >3 yr; BMM most important independent indicator of breast
cancer mortality; German study—>800 patients followed for >4 yr; BMM independent prognostic indicator for distant
disease-free survival (DFS) and cancer-related mortality in multivariate analysis (including nodal status, estrogen receptor
(ER)/progesterone receptor (PR) expression, tumor grade, and lymphovascular invasion); study—follow-up of 12 yr;
BMM significant in univariate analysis but not predictive in multivariate analysis; study—>200 patients followed for 4
yr; BMM not significant for overall survival
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| Disease-free survival: Cornell University study—375 breast cancer patients, predominantly stage I to II, with median 8-yr
follow-up; incidence of BMM 35%; BMM independent of lymph node status, tumor diameter, and ER/PR status; BMM significant
predictor of DFS in univariate and multivariate analysis
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| Correlation with lymph node status: Braun et al—node-negative and BMM-negative patients had survival of 100%;
node-positive and BMM-positive patients have poor survival rates; node-positive and BMM-negative patients had similar
survival rates to node-negative and BMM-positive patients; BMM as predictive as nodal status, but also independent
of nodal status; data—2 studies show immunohistochemistry (IHC) of axillary lymph nodes and BMM independent
prognostic indicators; Cornell University study—in 125 patients with stage I to III disease, incidence of BMM positivity
33% and SLNB positivity 42% (including IHC); BMM and SLNB independent prognostic indicators; 14% of patients
SLNB negative but BMM positive; kappa statistical analysis showed little correspondence between BMM and SLNB;
bone marrow aspiration may serve as complement to SLNB
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| Tumor recurrence: Cote et al—time to recurrence of metastases shorter for BMM-positive patients
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| Cornell University study: 43 patients underwent lumpectomy or mastectomy, SLNB or ALND, and bone marrow aspiration;
tumor board made treatment recommendations blinded and unblinded to BMM status; 23% of patients BMM positive;
tumor size and patient age same for BMM-negative and BMM-positive patients; change in treatment
recommendations after BMM status unblinded—recommendations did not change for BMM-negative patients; for
BMM-positive patients, no change for 2 patients for whom chemotherapy already recommended, recommendations for 3
patients changed from tamoxifen to chemotherapy, and for 1 patient, from observation to chemotherapy; 40% of BMM-
positive patients and 67% of BMM-positive, node-negative patients had recommendations changed after unblinding of
BMM status; changes predominantly in node-negative patients with small tumors
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| Bone marrow status over time: 22% of BMM-negative patients become BMM positive after chemotherapy; 42% of
BMM-positive patients become BMM negative after chemotherapy; patients BMM negative after chemotherapy do
much better than those who are BMM positive; suggests presence of occult malignant cells for unknown period of time
that have potential to become clinically significant
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| Peripheral blood testing: Krag et al—21 patients with breast cancer had peripheral blood analyzed before and after surgery
at intervals of ≤14 days; at time of surgery, 95% of patients had circulating epithelial cells (assumed to be cancer
cells); at 14 days, 30% remained positive; number of circulating epithelial cells independent of tumor size, node status,
and histologic grade; Beitsch et al—at time of surgery, 95% to 100% of patients had circulating epithelial cells; 52% of
controls (patients with fibroadenomas) had circulating epithelial cells
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| ABLATION THERAPY IN BENIGN AND MALIGNANT BREAST DISEASE— Dr. Simmons
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| Ablative techniques: important to perform pre-ablation core biopsy to clarify diagnosis and test for markers (eg, ER/PR,
HER-2/neu); all current techniques image-guided (US, stereotaxis, or MRI), which allows 3-dimensional localization of tumor
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Radiofrequency (RF) Ablation
| Mechanism: destruction of breast cancer using heat; probe itself not source of heat; heat generated by high-frequency alternating
current that causes movement and frictional heat in ions of surrounding tissues
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| Probe properties: hollow needle containing wires that can be extruded inside tumor; adjustable 15-gauge probe allows
zone of ablation of 1 to 5 cm
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| Procedure: used with US; takes 5 to 7 min to reach target temperature of 95°C; 15 min at target and 1 min cooldown; tissue
then resected and sent to pathology; chalky yellow tissue represents area of destruction; surrounding pink/red ring
represents edge of ablation zone
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| Pathologic analysis: in addition to standard hematoxylin and eosin stain, reduced nicotinamide adenine dinucleotide (NADH)
tumor viability stain performed that shows whether cells dead
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| Literature review: Tri-institutional study—in 30 patients who underwent RF ablation followed by resection, 87% ablation
achieved; ablation shown to be unsuitable for patients undergoing neoadjuvant chemotherapy; 3 patients had larger
tumors than expected, highlighting limitations of US; Jeffrey et al—in patients with local advanced breast cancer who
underwent RF ablation followed by mastectomy, 80% ablation achieved
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Cryoablation
| Background: probe inserted through incision under local anesthetic; freezing process involved in cryoablation acts as anesthetic,
resulting in pain-free procedure that can be performed while patients fully awake; can see freezeball incorporate
fibroadenoma or cancer on US, and its size and proximity to skin; if too close to skin, inject local anesthetic or saline to
create separation between skin and freezeball to allow accommodation of even superficial fibroadenomas
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| Technique: perform core biopsy (speaker does not do cryoablation if core biopsy suggests phyllodes tumor); incision created
for 2-mm probe under local anesthetic; probe has sharp tip for penetration of dense tissue; using US, probe centered within tumor
and freezeball begins to form (ice crystals can be seen forming on US); preferable to incorporate 5-mm rim if tumor cancerous,
less if fibroadenoma; probe removed and band aid applied; most patients do not need analgesics; over 12 mo,
fibroadenoma will shrink and disappear; resection performed if tumor cancerous
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| Cryoablation of fibroadenomas: Kaufman et al—multi-institutional series of 50 patients; fibroadenoma median size 2
cm (range ≤4.2 cm); at 12 months, 95% of patients had complete resolution of fibroadenomas
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| Cryoablation of breast cancers: study—27 patients with T1 invasive breast cancer with mean size of 1.2 cm (range ≤2
cm); (important to wait 1 wk between cryoablation and resection for necrosis to be seen); SLNB performed where appropriate
without problems; patients required no narcotics for cryoablation procedure and had no complications; in tumors <1.5
cm (restricted to ductal and medullary tumors and no extensive intraductal carcinomas), 100% ablation achieved; 78% ablation
achieved overall; for all tumors <1 cm, 100% ablation achieved
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Laser Ablation
| Mechanism: image-guided by MRI or stereotaxis; laser generates heat that destroys cancer; can be used for calcifications (RF
and cryoablation use US, which cannot show calcifications)
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| Histologic analysis of tissue: series of rings visible; first ring represents vaporization of tissue by laser tip; next ring
“pseudoviability zone”, which looks like live cancer but represents outer zone of ablation
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| BREAST CANCER: NEW WAYS TO BLOCK ESTROGEN —Helen K. Chew, MD, Assistant Professor of Internal Medicine
and Director of Breast Cancer Program, University of California, Davis, School of Medicine
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| Strategies for blocking estrogen in postmenopausal women: aromatase inhibition; blocking estrogen receptors through
selective estrogen receptor modulators (eg, tamoxifen [Nolvadex]) or estrogen receptor downregulators (eg, fulvestrant
[Faslodex])
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| Arimidex, Tamoxifen Alone, or in Combination (ATAC) trial: largest early breast cancer trial, with >9000 women
worldwide randomized to anastrazole (Arimidex) alone, tamoxifen alone, or combination; anastrazole group had better
DFS than tamoxifen group (statistically significant); no difference between combination group and tamoxifen group;
fewer contralateral breast cancers in anastrazole group than tamoxifen or combination groups (statistically significant);
updated data—anastrazole DFS 87%; tamoxifen DFS 85%; anastrazole will likely give very small additional benefit to
patients, particularly those with low-risk disease
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| National Cancer Institute of Canada study: >5000 patients randomized to letrozole or placebo as extended therapy after
5 yr of tamoxifen therapy; patients postmenopausal at cessation of tamoxifen therapy; results—letrozole group had better
DFS than placebo group (absolute difference 6%, projected for 4 yr); for all categories of recurrence (local, regional,
distant, and contralateral breast cancers), fewer events occurred in letrozole group; no difference between letrozole group
and placebo group in overall survival (no patients received intended 5-yr course of letrozole because trial stopped early);
more side effects reported with letrozole, including hot flushes, arthralgia, myalgia, and vaginal bleeding
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| Sequencing therapy study: >5000 postmenopausal women who had been on tamoxifen therapy for 2 or 3 yr randomized
to complete 5 yr of tamoxifen therapy or exemestane (Aromasin) for remainder of 5-yr period; results—statistically significant
difference in DFS for women who switched to exemestane; no difference between groups in overall survival
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| Clinical implications: no comparison data to show which strategy incorporating aromatase inhibitors optimal; no demonstrated
survival benefit for aromatase inhibitors, but all 3 trials showed improved DFS; anastrazole approved by Food and
Drug administration for postmenopausal women with hormone-sensitive disease; total duration of treatment unknown;
choice of whether to use aromatase inhibitor should be made after discussions with patient about side effects and cost
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Educational Objectives
| The goal of this program is to educate the listener about issues in breast cancer. After hearing and assimilating this program,
the clinician will be better able to:
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 | 1. Discuss the use of ultrasonography in breast surgery practice.
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| 2. Summarize the empiric evidence supporting the use of bone marrow aspiration as a prognostic indicator for metastatic
breast cancer.
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| 3. Use bone marrow aspiration in patient evaluation.
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| 4. Discuss the potential applications of ablation therapy for the treatment of benign and malignant breast disease.
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| 5. Critique the role of aromatase inhibitors in breast cancer therapy.
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Discussed on This Program
Anaritide acetate [Auriculin]
Anastrozole [Arimidex]
Exemestane [Aromasin]
Fulvestrant [Faslodex]
Letrozole [Femara]
Tamoxifen citrate [Nolvadex]
Suggested Reading
Agnese DM, Burak WE Jr: Ablative approaches to the minimally invasive treatment of breast cancer. Cancer J
11(1):77, 2005; Baum M et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant
treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet
359(9324):2131, 2002; Beitsch PD, Clifford E: Detection of carcinoma cells in the blood of breast cancer patients. Am J
Surg 180(6):446, 2000; Braun S et al: A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med
353(8):793, 2005; Braun S et al: Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or
III breast cancer. N Engl J Med 342(8):525, 2000; Burak WE Jr et al: Radiofrequency ablation of invasive breast carcinoma
followed by delayed surgical excision. Cancer 98(7):1369, 2003; Coombes RC et al: Safety of exemestane in the
Intergroup Exemestane Study. J Clin Oncol 23(13):3171, 2005; Coombes RC et al: A randomized trial of exemestane after
two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med
350(11):1081, 2004; Gebauer G et al: Micrometastases in axillary lymph nodes and bone marrow of lymph node-negative
breast cancer patients--prognostic relevance after 10 years. Anticancer Res 23(5b):4319, 2003; Goss PE et al: Randomized
trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings
from NCIC CTG MA.17. J Natl Cancer Inst 97(17):1262, 2005; Goss PE et al: A randomized trial of letrozole in postmenopausal
women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349(19):1793, 2003;
Howell A et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years'
adjuvant treatment for breast cancer. Lancet 365(9453):60, 2005; Kaufman CS et al: Office-based cryoablation of breast
fibroadenomas with long-term follow-up. Breast J 11(5):344, 2005; Kaufman CS et al: Cryoablation treatment of benign
breast lesions with 12-month follow-up. Am J Surg 188(4):340, 2004; Naume B et al: The prognostic value of isolated tumor
cells in bone marrow in breast cancer patients: evaluation of morphological categories and the number of clinically significant
cells. Clin Cancer Res 10(9):3091, 2004; Sabel MS et al: Cryoablation of early-stage breast cancer: work-in-
progress report of a multi-institutional trial. Ann Surg Oncol 11(5):542, 2004; Trocciola SM et al: Do bone marrow micrometastases
correlate with sentinel lymph node metastases in breast cancer patients? J Am Coll Surg 200(5):720, 2005;
Wiedswang G et al: Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer.
J Clin Oncol 21(18):3469, 2003; Yu JJ et al: Bone marrow micrometastases and adjuvant treatment of breast cancer.
Breast J 10(3):181, 2004.
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 following
has been disclosed: Dr. Simmons is a consultant for Sanarus Medical, Inc. and Veridex, LLC.
Dr. Simmons was recorded January 26-29, 2005, at the 33rd Annual Phoenix Surgical Symposium, sponsored by the Maricopa
Integrated Health System and the Phoenix Surgical Society and held in Scottsdale, Arizona. Dr. Chew was recorded
September 19, 2004, at General Surgery 2004—26th Annual Postgraduate Course sponsored by the University of California,
Davis, Health System and held in Olympic Valley, California. The Audio-Digest Foundation thanks the speakers
and the sponsors for their cooperation in the production of this program.
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