BREAST CANCER
| TARGETED TREATMENTS FOR BREAST CANCER— Kelly K. Hunt, MD, Professor of Surgery, and Chief, Surgical
Breast Section, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX
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| Effects of optimal therapy on mortality: Early Breast Cancer Trialists’ Collaborative Group (EBCTCG; 2000) estimates
odds of death reduced 10% by local therapy, 30% by tamoxifen, 20% by anthracycline-based chemotherapy;
overall reduction in odds of death 50%; addition of aromatase inhibitors, taxanes, and dose-dense therapy expected to
further decrease odds of death
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| Biologic targets: include steroid hormone receptor pathway (eg, estrogen) and angiogenesis; many used in diseases
other than breast cancer; need to determine in which patients these targets significant factors in progression of disease
and therefore useful tools in treatment
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| Mechanisms of action of hormonal therapies: block estrogen action (tamoxifen, toremifene, and other antiestrogens);
block estrogen synthesis through ovarian ablation (surgical; medical; inhibition or inactivation of aromatase);
other mechanisms (progestins, androgens, and estrogens)
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| Endocrine therapy: estrogen receptor (ER) prognostic and predictive marker; higher response rate to estrogen-related
therapy in patients with ER-positive (ER+) and/or progesterone receptor–positive (PR+) tumors than in those with ER-
or ER+/PR- tumors; premenopausal and postmenopausal patients benefit
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 | Tamoxifen: EBCTCG study found tamoxifen more effective in ER+ disease; 5-yr course of tamoxifen superior to 1 to 2
yr; associated with 31% reduction in annual breast cancer mortality; cumulative reduction in mortality more than twice
as big at 15 yr than at 5 yr; consider risks and benefits of tamoxifen when counseling patients; benefits—can decrease
relapse rate and improve survival; decreases incidence of contralateral disease; decrease serum concentrations of total
cholesterol and low-density lipoprotein (LDL); may increase and stabilize bone density in postmenopausal women;
risks—include irregular menses, menopausal symptoms, ocular toxicity, and increased cataract formation, thromboembolic
events, leukopenia, endometrial cancer, and uterine sarcomas
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| Aromatase inhibitors: interfere with estrogen synthesis; include selective and nonselective inhibitors; several trials looking
at adjuvant therapy with aromatase inhibitors show benefit in postmenopausal patients; ideal time to begin aromatase
inhibitor therapy or sequencing with tamoxifen currently unknown; Arimidex or Tamoxifen Alone or in
Combination (ATAC) trial—anastrozole better than tamoxifen in all study end points, including disease-free survival,
time to recurrence, contralateral breast cancer events, time to distant recurrence, overall survival, and time to
death from breast cancer; anastrazole associated with more favorable adverse-event profile than tamoxifen; patients
taking anastrazole had fewer drug-related adverse events and side effects leading to withdrawal; anastrazole associated
with fewer hot flushes, less vaginal bleeding, and fewer thromboembolic events than tamoxifen; fracture rates higher
in patients taking anastrazole; several aromatase inhibitors available; consider using aromatase inhibitor as first-line
therapy in postmenopausal patients
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| Adjuvant hormonal therapy: treatment options—consider ovarian ablation or tamoxifen in premenopausal patients; consider
tamoxifen or aromatase inhibitors in postmenopausal patients
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| Trastuzumab: targets herceptin (HER)-2; mechanisms of action not completely understood; proposed mechanisms include
cell cycle arrest, inhibition of cell signaling, inhibition of vascular endothelial growth factor (VEGF) production,
and inhibition of HER-2 receptor shedding into systemic circulation; data show—monotherapy improves outcome; in
combination with chemotherapy, trastuzumab improved response rate, duration, time to progression, and overall survival
rate; neoadjuvant trastuzumab (study)—in patients with operable HER-2 receptor-positive disease who received chemotherapy
plus weekly trastuzumab, pathologic complete response rates increased to 65.2% from 26.3% with chemotherapy
alone; unknown whether this translates to improved survival; neutropenia grade 4 occurred more often in patients
receiving trastuzumab; no clinical cardiac toxicity observed
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| Bevacizumab: targets VEGF receptor; study data—randomized study looked at paclitaxel vs paclitaxal plus bevacizumab
as first-line therapy for HER-2–positive patients with locally recurrent or metastatic breast cancer; patients given
bevacizumab had more favorable progression-free survival and overall survival; toxicity associated with bevacizumab
delays progression of disease included high blood pressure (BP), bleeding episodes, neuropathy, fatigue, and proteinuria;
summary—bevacizumab delays progression of disease significantly in patients with metastatic breast cancer when used
in combination with first-line chemotherapy; side effects suggest careful selection of patients and appropriate monitoring
during treatment
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| RADIATION AFTER BREAST CANCER —Shawna C. Willey, MD, Assistant Professor of Surgery, Georgetown University
School of Medicine, Washington, DC
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| Whole-breast and postmastectomy radiotherapy
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| Locoregional recurrence: risk for recurrence decreased in ductal carcinoma in situ (DCIS) and after breast-conserving therapy
(BCT) in patients receiving radiotherapy; locoregional recurrence defined as recurrence of disease in regional lymph
nodes, internal mammary nodes, supraclavicular nodes, axillary nodes, or in skin as well as in breast tissue
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| Morbidity: associated with whole-breast or postmastectomy radiotherapy; may continue for years after treatment; in deciding
whether to use radiotherapy, assess risk for recurrence in individual patient and determine whether risk greater
than that of radiotherapy-associated morbidity
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| Risk for recurrence: within same breast, 1% to 2% per year; majority of recurrences in same area as initial cancer, and
greater number of recurrences located in same quadrant; negative margins important in preventing recurrence; chances
of having recurrence in other area of breast smaller; differentiate between recurrence and new primary tumor (behaves
differently from recurrent disease and has different genetic makeup; associated with better prognosis); studies suggest
risk for development of contralateral disease only slightly higher than if patient had not had breast cancer
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| Postmastectomy radiotherapy: early studies—showed decreased overall survival rate, despite decreased incidence
of death due to breast cancer; most deaths due to cardiac toxicity; irradiation of chest wall, especially on left side, resulted
in decreased survival; later meta-analysis— included newer radiotherapy techniques; found fewer deaths due to breast
cancer, but more cardiac-related deaths, resulting in equivalent survival rate; several studies—concluded post-mastectomy
radiotherapy results in two-thirds reduction in locoregional recurrence and improved 10-yr overall survival; however,
these studies done before development of sentinel lymph node (SLN) biopsy technique and lacked standardized
axillary dissections (45% of recurrences in axilla); recent large meta-analysis—looked at data on 15 yr of follow-up on
42,000 women; looked at all radiotherapy after breast cancer; patients who had breast-conserving surgery had 19% decrease
in recurrence and 5% reduction in mortality; patients who had mastectomy had similar risk for recurrence and
mortality; take-home lesson—if patient’s risk for locoregional recurrence >20%, recommend radiotherapy to improve
survival; consensus statements from major organizations—recommend radiotherapy if patient has ≥4 positive lymph
nodes or if patient has locally advanced primary tumor >5 cm and to minimize radiation to heart and lungs; postmastectomy
radiotherapy improves survival in patients with persistent locoregional disease, where intended target irradiated,
and no treatment-related mortality occurs; most benefit from radiotherapy—seen in patients with locally advanced but
not metastatic disease, or with metastatic disease cured by systemic therapy
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| Partial breast irradiation: most recurrences after breast-conserving surgery occur within same quadrant or within
lumpectomy bed; DCIS or invasive cancer, if margin around lumpectomy bed >10 mm, recurrence rate small and benefit
of radiotherapy also small; avoids toxicity of whole breast irradiation; partial breast irradiation uses external beam radiation;
intraoperative radiotherapy—single dose of radiation to lumpectomy bed after surgical excision; interstitial
brachytherapy—longest follow-up studies using this method; studies show acceptable recurrence rate at 10 yr; literature
reports of 709 cases with 2-yr follow-up show recurrence rate <4% (known that in-breast recurrence rate highest in
first 2 yr after lumpectomy); multicatheter method found to have 1% recurrence rate at 5 yr, with excellent cosmetic results;
MammoSite delivery system—radiation delivered through balloon into lumpectomy cavity after surgical excision
of tumor
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| Adverse effects of radiotherapy: short-term effects—include fatigue and skin erythema; long-term effects—breast
edema, chronic pain syndromes, chronic lymphedema; radiation pneumonitis, rib fractures; cardiac toxicity, lung cancer, sarcoma,
and contralateral breast cancer still affecting patients, even 15 yr later
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| SURGICAL MANAGEMENT OF DUCTAL CARCINOMA IN-SITU —David R. Farley, MD, Professor of Surgery,
Mayo Clinic College of Medicine, Rochester, MN
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| Ductal carcinoma in situ (DCIS): definition—proliferation of malignant cells confined to mammary ducts, without
microscopic evidence of invasion through basement membrane; stage I breast cancer; incidence—≈20% of newly diagnosed
breast cancers; incidence increasing (7.7 times higher in 2005 than in 1985); incidence high in younger women;
mammography—>90% of cases diagnosed with mammography; palpable soft tissue mass rare but can occur with Paget’s
disease or any nipple discharge; classification—nuclear grade most important for surgeons; separated into high, intermediate,
and low grades; necrosis indicates presence of tumor withdrawing blood supply; architectural pattern different in each
case; natural history—heterogeneous disease; clinical pattern and imaging unpredictable; histology difficult; biomarkers and
gene expression still uncategorized
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| Diagnosis: mammography—tree-like branching pattern of calcifications indicates high-grade lesion; coarse or fine
granular calcifications indication of lower-grade disease; find high-grade lesions; 90% of lesions calcified because tumor
outgrowing blood supply (develop necrosis and calcify); mammography good tool to predict high-grade DCIS, less successful
with low-grade disease; magnetic resonance imaging (MRI)—sensitivity high in invasive cancer; in DCIS,
sensitivity 40% to 100% and specificity 37% to 97%; morphologic features less defined; false negatives more frequent;
some lesions may not enhance
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| Mastectomy: most women prefer BCT to mastectomy; DCIS on continuum, with some cases localized and some diffuse;
recommend mastectomy in patient with high-grade DCIS throughout breast; consider whether excision of tissue and negative
margins possible; prefer mastectomy unless DCIS closely confined to quadrant; if no palpable mass, excise tissue located
by wire localization and obtain x-ray to find calcifications; pathologist performs fresh-frozen section analysis to
check margins; recommend mastectomy if negative margins cannot be obtained; use specimen radiography to determine
surgical margins; study—455 patients with DCIS who did not receive radiation therapy; looked at risk for local recurrence;
4 factors predicted disease recurrence, 1) margin width (wide margins associated with reduced risk for recurrence;
<1-cm margin increased risk for recurrence by 5.4 times), 2) age of patient (younger patient, more likely tumor would recur),
3) grade of lesion (more advanced lesions more likely to recur), and 4) lesion size (larger lesion more likely to recur);
another study—of 103 patients with DCIS who received radiotherapy, found 13 recurrences (9 cases of DCIS and 4 of
invasive adenocarcinoma) at 5-yr follow-up; increased risk for recurrence associated with positive margins, advanced
grade of lesion, and younger age of patient; conclude only 7% risk for recurrence with negative margins and appropriate
radiotherapy, and 31% chance of recurrence if margins positive; radiotherapy—decreases risk for recurrence in patients
who have breast-conserving surgery, and mortality same as for mastectomy; indications for mastectomy—diffuse disease
located in >1 quadrant; disease in multicentric areas, so that clear margins not possible; local failure after BCT; patient
prefers mastectomy
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| Breast-conserving therapy: when leaving breast tissue behind, consider mammography has error rate (indicates localized
lesion when disease more diffuse or underestimates size of lesion) and pathology may be inadequate in determining
whether margins clear; study—of 707 patients with DCIS treated with BCT, recurrence of disease in 74, and 34 of those
had invasive cancer (compared to 1% local recurrence in patients who had mastectomy); criteria for BCT—limited disease;
clear margins confirmed histologically; avoid leaving suspicious residual calcifications; physical examination and
mammography easy to interpret; patient prefers BCT
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| Axillary staging in DCIS: studies suggest rate of positive lymph nodes very low; however, core needle biopsy associated
with false-negative rate (invasive adenocarcinoma identified in 66 patients with diagnosis of DCIS on core needle
biopsy); positive SLN biopsy more likely in patients with high-grade DCIS, mass on mammography, or invasion suspected
from core needle biopsy; SLN biopsy recommended in patients who received only core needle biopsy preoperatively;
risk factors for occult invasion include younger age, high-grade lesion, primary lesion >4 cm, or core needle
biopsy; most positive SLNs contain micrometastatic disease found only with immunohistochemistry
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| Postoperative radiation therapy: study found availability or recommendation of radiotherapy for patients with
DCIS varied according to institution; currently, no standardized guidelines for use of postoperative radiotherapy in patients
with DCIS; studies suggest radiotherapy beneficial to patients with DCIS in terms of risk for local recurrence; recommend
selective use of wide local excision without radiotherapy (consider in patients at low risk for failure, eg, older
woman with low-grade lesion and wide margin)
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| Tamoxifen: studies suggest tamoxifen beneficial in patients who have recurrence of DCIS; limited benefit in ipsilateral disease
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Educational Objectives
| The goal of this activity is to provide a greater understanding of the targeted treatments for breast cancer, irradiation
after breast surgery, and operative management of ductal carcinoma in-situ (DCIS). After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Explain the rationale for targeted treatments for breast cancer.
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| 2. Describe the use of endocrine therapies and angiogenesis inhibitors in treating breast cancer.
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| 3. Review the effect of radiation therapy on locoregional recurrence of breast cancer.
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| 4. Cite the difficulties in diagnosing DCIS.
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| 5. Review the operative management of DCIS.
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Discussed on This Program
Anastrozole [Arimidex]
Bevacizumab [Avastin]
Paclitaxel [Onxol, Paxene, Taxol, Abraxane]
Tamoxifen citrate [Nolvadex]
Toremifene citrate [Fareston]
Trastuzumab [Herceptin]
Suggested Reading
Benitez PR et al: Preliminary results and evaluation of MammoSite balloon brachytherapy for partial breast irradiation
for pure ductal carcinoma in situ: a phase II clinical study. Am J Surg. 192:427, 2006; Chakrabarti J et al:
Accuracy of mammography in predicting histological extent of ductal carcinoma in situ (DCIS). Eur J Surg Oncol.
Jul 25, 2006; Harris EE et al: Late cardiac mortality and morbidity in early-stage breast cancer patients after
breast-conservation treatment. J Clin Oncol. 24:4100, 2006; Huo L et al: Predictors of invasion in patients with
core-needle biopsy-diagnosed ductal carcinoma in situ and recommendations for a selective approach to sentinel
lymph node biopsy in ductal carcinoma in situ.Cancer. 107:1760, 2006; Khatcheressian JL et al: American Society
of Clinical Oncology 2006 Update of the Breast Cancer Follow-Up and Management Guidelines in the Adjuvant
Setting. J Clin Oncol. Oct 10, 2006; Lagios MD et al: Prospective study of wide excision alone for ductal carcinoma
in situ of the breast. J Clin Oncol. 24:3809, 2006; Nose T et al: A Pilot Study of Wider Use of Accelerated
Partial Breast Irradiation: Intraoperative Margin-directed Re-excision Combined with Sole High-dose-rate Interstitial
Brachytherapy. Breast Cancer. 13:289, 2006; Poleshuck EL et al: Risk factors for chronic pain following breast
cancer surgery: a prospective study. J Pain. 7:626, 2006; Sabel MS: Locoregional therapy of breast cancer: maximizing
control, minimizing morbidity. Expert Rev Anticancer Ther. 6:1281, 2006; Sakr R et al: Ductal carcinoma
in situ: value of sentinel lymph node biopsy. J Surg Oncol. 94:426, 2006; Schouten van der Velden AP et al:
Clinical presentation and surgical quality in treatment of ductal carcinoma in situ of the breast. Acta Oncol. 45:544,
2006; Shigematsu N et al: Radiation therapy after breast-conserving surgery. Radiat Med. 24:388, 2006;
Taghian AG et al: Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm
or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from
five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 24:3927, 2006;
Voth M et al: Local recurrence of breast cancer after MammoSite brachytherapy. Am Surg. 72:798, 2006; Yen
TW et al:Physician recommendations regarding tamoxifen and patient utilization of tamoxifen after surgery for
ductal carcinoma in situ. Cancer. 100:942, 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 faculty reports nothing to disclose.
Dr. Hunt was recorded September 16-17, 2005, in Napa, CA, at the 27th Annual Postgraduate Course in General
Surgery 2005, sponsored by the University of California, Davis, Health System, Department of General Surgery, and
Continuing Medical Education. Drs. Willey and Farley were recorded April 27-29, 2006, in Charleston, SC, at the
35th Annual Postgraduate Course in Surgery, sponsored by the Medical University of South Carolina, Department of
Surgery. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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