ADVANCES IN BREAST CANCER
| PARTIAL BREAST IRRADIATION IN THE MANAGEMENT OF BREAST CANCER —Megan Baker Ruppel, MD,
Assistant Professor of Surgery, Medical University of South Carolina, and Medical Director, Comprehensive Breast
Care, Hollings Cancer Center, Charleston
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| Radiotherapy: essential component of breast conservation therapy (BCT); reduces risk for local regional recurrence
(some data suggest may improve survival); principles of therapy—uses tangential photon fields to treat breast tissue
but limits visceral organ injury; also can give additional boost to tumor bed
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 | Whole breast irradiation: standard therapy 40 Gy to 50 Gy delivered over 6 wk; tumor boost delivered by brachytherapy
catheter, electron beams, or conformal photon field arrangement; technique—external beam arranged in tangents
across chest wall, excluding lung and heart (left-sided lesions); treatment borders extend from sternum to midaxillary
line, and from sternomanubrial junction down to below inframammary sulcus; data on ductal carcinoma in situ
(DCIS)—local recurrence rates dramatically decreased with whole breast irradiation plus lumpectomy, compared to
lumpectomy alone (source, National Surgical Adjuvant Breast and Bowel Project [NASBP]); data on stages I and II
invasive cancer—compared to mastectomy, BCT with radiation therapy (XRT) shows slightly higher local recurrence
rates but equivalent survival rates; BCT alone vs BCT with XRT shows addition of XRT reduces local recurrence;
decrease in local recurrence in invasive disease more significant than seen in DCIS; reasons for changing
standard practice—compliance; local recurrence rate with lumpectomy ≈30%; NSABP data show 76% of patients
with recurrence have recurrence at, or near, lumpectomy site; recurrences elsewhere associated with better prognosis;
rate of elsewhere recurrence similar to rate of contralateral breast occurrences; data on recurrence after whole breast
irradiation show majority of recurrence at site of lumpectomy, few with recurrence outside of lumpectomy site in
same breast, and remainder recurrences at distant site (bone or other organs); factors for failures elsewhere after
whole breast XRT—extensive intraductal component; invasive lobular carcinoma; tumor >4 cm
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| Partial breast irradiation (PBI): rationale—whole breast irradiation fails to decrease elsewhere occurrences in breast,
so should direct XRT to place of greatest impact (tumor bed and surrounding area); protocol—equivalent dose delivered
in accelerated format (total dose in 5-10 days); data on stages 0, I, and II breast cancers—low local recurrence
rates (0%-2%); all studies required clear surgical margins; no large prospective randomized trial with >5-yr
data currently available; American Society of Breast Surgeons Consensus Statement on PBI—indications for PBI
include tumors <3 cm, node-negative disease, and DCIS or invasive carcinoma; timing—XRT in PBI given 5 to 20
days after surgery, before any adjuvant therapy or hormonal therapy; delivery—data show most equivalent distribution
of radiation dose obtained using brachytherapy catheters; 3-dimensional conformal technique another common
method for delivery (does not require insertion of foreign body; technologically more difficult and costly);
MammoSite—implantable afterloading balloon device; catheter inserted in area of lumpectomy cavity; patients receive
targeted XRT twice daily for 5 days; surgical considerations include distance from skin to cavity (>7 mm reduces
skin injury), compatibility of cavity size and shape with balloon, and peri- and postoperative antibiotics while
catheter in place; surgical placement of MammoSite—open cavity technique done at time of lumpectomy (lacks
pathology information and requires removal if need to go back to get clear margins; technique seldom used); scar
entry technique (placed after pathology finalized; allows for skin excision if added thickness needed); ultrasonography-guided
technique (no new suture line; no opportunity to improve on skin thickness); choice of balloon size and
shape (round vs oval) important; rate of infection 11%; significant seroma rate (but persistent seroma rates improve);
90% of patients report good to excellent cosmesis
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| Studies: Radiation Therapy Oncology Group (RTOG)/NSABP-39— comparing PBI to WBI; results not available;
intraoperative radiotherapy—delivered before or after excision; concern about wound healing issues; concern that
intraoperative dose not appropriate when tumor larger than expected; good to excellent cosmesis; long-term results
pending
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| WHAT SURGEONS SHOULD KNOW ABOUT ADJUVANT SYSTEMIC THERAPY —Merrick I. Ross, MD, Professor
of Surgery, and Chief, Melanoma Section, MD Anderson Cancer Center, University of Texas, Houston
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| General: significant improvement in mortality rates for breast cancer; primarily due to screening mammography (early
diagnosis) and more effective therapies (addition of adjuvant systemic therapies)
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| Adjuvant therapy: local-regionally based (adjuvant XRT; focus on breast, chest wall, and lymphatics); systemic
therapy (chemotherapy and hormone therapy) treats micrometastatic disease throughout body; considerations—
estimated risk for recurrence and death in individual patient; benefits of available therapies; toxicities of therapies;
menopausal status; underlying comorbidities
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| Prognostic and predictive markers: prognostic markers identify certain patients at risk for recurrence and death;
predictive markers identify patients who can benefit from specific therapy; certain markers predict adverse events related
to specific therapies; prognostic factors—tumor size; nodal status; grade; lymphovascular invasion; ploidy;
ERBB2 (formerly HER2 or HER2/neu) positivity (bad prognostic factor); estrogen receptor (ER) positivity (favorable
factor); gene arrays; predictive factors—ERBB2 predicts response to trastuzumab (Herceptin); ER status predicts response
to hormone therapies; gene arrays predictive of responses to certain therapies; gene signatures for toxicities to
certain therapies
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| Historical perspective: early observations that systemic therapy important; early markers for distant disease were tumor
size and nodal involvement; today, with more node-negative patients identified, risk for distant relapse still 20%
to 30%, suggesting micrometastatic disease occurs in absence of nodal metastases; in 1970s, cyclophosphamide,
methotrexate, and fluorouracil (CMF) became gold standard (based on meta-analysis that showed significant improvement
in node-positive and node-negative patients); next 20 yr focused on anthracycline-based therapies (doxorubicin
[Adriamycin] and epirubicin), comparing them to standard CMF regimen that showed equivalence for relapse-free
survival and overall survival, but regimen better tolerated; meta-analysis (2005)—looked at anthracycline-based
therapy compared to CMF; showed improved hazard ratios with anthracycline therapy (vs CMF), and showed improvement
in recurrence and overall survival across all prognostic groups; meta-analysis (Lancet, 2005)—15-yr
summary showed that 6 mo of anthracycline-based therapy reduces death rate by 38% for young patients and 20% for
patients between ages 50 yr and 69 yr (benefits seen regardless of hormone therapy, receptor status, or prognostic
groups); tamoxifen-related therapies reduce death rate by 31%, regardless of chemotherapy, patient age, or other prognostic
factors; taxanes (paclitaxel [eg, Taxol] and docetaxel [Taxotere])—data show relatively consistent improvement
in disease-free and overall survival with adjuvant taxanes, predominantly in patients with positive nodes;
increased toxicity when administered concomitantly with anthracyclines; no consensus on optimal sequence or which
taxane to use; limited data in patients with node-negative disease; patients that benefit from adjuvant chemo- and
hormone therapy—meta-analysis showed all patients with positive nodes <70 yr of age and high-risk patients with
node-negative disease benefit from chemotherapy; all patients of all ages with ER positivity and positive nodes and
high-risk patients with node-negative disease benefit from hormone therapy; many patients do not benefit at all; patients
with negative nodes and ER positivity (most common group of patients) most likely patients overtreated by systemic
therapy
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| Selective approach to chemotherapy: identify which group individual patient in (ie, those whom local therapy
will cure, those who will benefit from adjuvant systemic therapy, and those resistant to both); trial in Europe uses
fresh tissue to identify gene profiles that identify markers for distant metastases that would occur in <5 yr (as opposed
to patients who will never develop metastases); identifies 70 gene signatures, producing 2 biologic subsets within
same group of patients based on gene signature (good vs poor); better discrimination of prognostic groups than other
models that use clinical pathologic factors; can identify patients more specifically, to use adjuvant therapy in more rational
setting; Microarray in Node-Negative Disease May Avoid Chemotherapy (MINDACT) trial—assessed prognosis
using 70 gene risk assessment and clinical pathologic features; Trial Assessing Individualized Options for
Treatment (TAILORx)—uses Oncotype Dx technique (gene profiling on paraffin-embedded tissue), and patients assigned
to adjuvant therapy groups using Oncotype Dx Recurrence Score (RS); multivariant analysis—RS and other
prognostic factors; RS and poor differentiation have independent influence on overall survival
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| Targeting adjuvant therapy using predictive markers: selective estrogen receptor modulators (SERMs) for
premenopausal patients (tamoxifen, raloxifene, and toremifene); aromatase inhibitors for postmenopausal patients
(anastrozole, letrozole, and exemestane); fluorescent in situ hybridization (FISH) best way to identify ERBB2 overamplification
(amplification leads to overexpression of proteins on cell surface, increased cell division, and more aggressive
biology); trastuzumab first-line therapy used in ERBB2-positive metastatic disease; data show disease-free
survival benefits for patients receiving trastuzumab in addition to chemotherapy
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| CONTROVERSIES IN THE DIAGNOSIS AND TREATMENT OF PATIENTS WITH DUCTAL CANCER IN SITU
(DCIS)—Kelly M. McMasters, MD, PhD, Sam and Lolita Weakley Professor, and Chair of Surgical Oncology, University
of Louisville, School of Medicine, Louisville, KY
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| General: breast tissue comprised of ducts and lobules; DCIS starts in duct; DCIS also called intraductal carcinoma (different
from infiltrating ductal carcinoma); precancerous findings (Stage 0); increased incidence of DCIS with screening
mammography and biopsy of nonpalpable lesions (>15% of breast cancer cases); most often seen as microcalcifications
on mammogram; incidence of DCIS increases with age, but drops off with very advanced age; spectrum of disease—
normal duct lumen with benign proliferative changes; atypical ductal hyperplasia; DCIS; invasive carcinoma; 76% of
time, DCIS presents with microcalcifications, sometimes with soft tissue density, or mass, or both; palpable mass uncommon;
can present as Paget’s disease; on mammography, high-grade DCIS often accompanied by clear evidence of
suspicious calcifications; non–high-grade DCIS potentially more difficult to diagnose (can have calcifications that
mimic benign disease; biopsy often necessary); biopsy options—needle localization excisional breast biopsy; stereotactic
biopsy (sampling error possible with core needle biopsy under sterotactic guidance; upgrade rate [DCIS to invasive
cancer] of 10%-25%); upgrade rate with excisional biopsy exists, but much less than with needle biopsy;
stereotactic biopsy showing atypical ductal or lobular hyperplasia warrants excisional biopsy; atypical ductal hyperplasia
and DCIS can look similar under microscope (degree of changes potential focus)
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| Treatment options for DCIS: partial mastectomy alone, with radiation therapy, with radiation and hormonal therapy,
or total mastectomy; mastectomy—gold standard for therapy in ductal carcinoma; data show local recurrence
rate of 0% to 2%; overall survival good; partial mastectomy alone—local recurrence rate ≤40%; invasive cancer in
half of recurrences; lower recurrence rate with addition of XRT (invasive cancer in half of recurrences) and overall
survival of 96% to 100%; risk for additional surgery to remove positive margins; positive margin on specimen overrides
negative result found in sampled margins from cavity; negative margins important with respect to recurrence
rates
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| Classification: Van Nuys original classification—high-grade with necrosis, high-grade without necrosis; and low-
grade; local recurrence rate different between 3 groups; University of Southern California/Van Nuys prognostic index
(USC/VNPI)—size of DCIS tumor, margin width, grade and presence of necrosis, and patient age; with score of 4 to 6,
local excision alone potential therapy; with score of 10 to 12, mastectomy performed; with score of 7 to 9, if partial mastectomy
performed, should include XRT; speaker’s clinical practice—most patients get radiation therapy and tamoxifen
for ER-positive DCIS if doing partial mastectomy; lumpectomy alone for some patients with DCIS if patient older
with small areas of low-grade DCIS, absence or slight comedo-necrosis, and widely negative margins; hormonal
therapy—studies show hormonal therapy reduces risk for local recurrence and invasive and noninvasive cancer, compared
to excision alone and lumpectomy plus XRT; ER status now checked in DCIS because patients that benefit from
hormonal therapy had ER-positive DCIS; age and local recurrence—younger patients have higher recurrence rates;
mastectomy vs lumpectomy—mastectomy performed when large areas of DCIS present, with cosmetic concerns, multicentric
disease, and positive margins not amenable to reexcision; excision of affected margin safe (wait for healing) unless
multiple positive margins exist; no randomized trials comparing mastectomy to lumpectomy with XRT in DCIS, just
assumed by extrapolation that results equivalent; speaker encourages talking to patients about risk for local recurrence
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| DCIS and axillary lymph nodes: sentinel lymph node biopsy for DCIS not necessary; 98% to 99% cure rate without
axillary dissection; studies evaluating sentinel node biopsy with pure DCIS show immunohistochemistry evidence
of tumor cells in sentinel node in 12%, 13%, or 23% of patients (depending on study); these findings do not match
clinical reality (question whether true metastasis, clinically significant, or artifact); 1% of time, patients with pure
DCIS without microinvasion show up with axillary node metastases; question of what to tell patient if sentinel node
biopsy performed and positive results seen (do not order test unless know what to do with results); mastectomy cures
98% of patients with DCIS with axillary dissection; speaker recommends performing sentinel node biopsy in select
patients; risk (ie, lymphedema) associated with sentinel node biopsy; algorithm—if patient with excisional biopsy,
no sentinel node biopsy; if core needle biopsy diagnosis and doing lumpectomy, no sentinel node biopsy (can go back
later); if mastectomy for DCIS, do sentinel node biopsy (cannot go back later)
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Suggested Reading
American College of Radiology: Practice guideline for the breast conservation therapy in the management of invasive
breast carcinoma. J Am Coll Surg 205:362, 2007; American College Of Radiology: Practice guideline for the
management of ductal carcinoma in-situ of the breast (DCIS). J Am Coll Surg 205:145, 2007; Benitez PR et al: Five-
year results: the initial clinical trial of MammoSite balloon brachytherapy for partial breast irradiation in early-stage breast
cancer. Am J Surg 194:456, 2007; BlueCross BlueShield Association: Accelerated partial breast irradiation as sole
radiotherapy after breast-conserving surgery for early stage breast cancer. Technol Eval Cent Asses Program Exec Summ
22:1, 2007; Bovi J et al: Comparison of three accelerated partial breast irradiation techniques: Treatment effectiveness
based upon biological models. Radiother Oncol 84:226, 2007; Dodwell D et al: Radiotherapy following breast-conserving
surgery for screen-detected ductal carcinoma in situ: indications and utilization in the UK. Interim findings from the
Sloane Project. Br J Cancer 97:725, 2007; Hieken TJ et al: Predicting relapse in ductal carcinoma in situ patients: an
analysis of biologic markers with long-term follow-up. Am J Surg 194:504, 2007; Kraus-Tiefenbacher U et al: Intraoperative
radiotherapy (IORT) is an option for patients with localized breast recurrences after previous external-beam radiotherapy.
BMC Cancer 7:178, 2007; McArthur HL, Hudis CA: Adjuvant chemotherapy for early-stage breast
cancer. Hematol Oncol Clin North Am 21:207, 2007; Moran CJ et al: Role of sentinel lymph node biopsy in high-risk
ductal carcinoma in situ patients. Am J Surg 194:172, 2007; Narayanan S, Taylor I: Adjuvant systemic therapy for
operable breast cancer. Surgeon 5:101, 2007; Niehoff P et al: Breast irradiation with brachytherapy: approved techniques
and new concepts. Minerva Ginecol 59:377, 2007; Nuyten DS, van de Vijver MJ: Gene expression signatures
to predict the development of metastasis in breast cancer. Breast Dis 26:149, 2006-2007; Valenzuela M, Julian
TB: Ductal carcinoma in situ: biology, diagnosis, and new therapies. Clin Breast Cancer 7:676, 2007; Waljee JF,
Newman LA: Neoadjuvant systemic therapy and the surgical management of breast cancer. Surg Clin North Am 87:39,
2007.
Educational Objectives
| The goals of this program are to improve management of breast cancer via partial breast irradiation and adjuvant systemic
therapy for breast cancer and to identify controversies in the diagnosis and treatment of patients with ductal cancer
in situ (DCIS). After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss the use of whole breast irradiation (compared to partial breast irradiation) in the treatment of breast cancer.
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| 2. Describe the delivery methods used in partial breast irradiation.
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| 3. Explain prognostic and predictive markers for breast cancer.
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| 4. Discuss historical and current data on adjunctive therapy in the treatment of breast cancer.
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| 5. Describe diagnosis, treatment options, and classification of ductal carcinoma in situ (DCIS).
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the following has been disclosed: Dr. McMasters received honoraria and
grants from Schering-Plough and Johnson & Johnson.
Acknowledgements
Dr. Ruppel was recorded at the 36th Annual Postgraduate Course in Surgery, held April 12-14, 2007, in Charleston,
SC, and sponsored by the Department of Surgery, Medical University of South Carolina. Drs. Ross and McMasters were
recorded at Advances in Breast, Endocrine, and Cancer Surgery, held June 14-16, 2007, in Minneapolis, MN, and
sponsored by the University of Minnesota Medical School, Department of Surgery and Continuing Medical Education.
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