Transcript Slide 1

San Antonio Breast Cancer Symposium
2006 Highlights – Breast Surgery
Frederick M. Dirbas, M.D.
Assistant Professor of Surgery
Stanford Cancer Center
Breast Conservation +/- RT

Abstract 29, Intergroup Study E5194:
Local Excision Without Radiation for
Selected Patients with DCIS
 Abstract 11, CALGB Study: Tamoxifen +/RT in Women ≥70 with Breast Cancer
Abstract 29, Intergroup* Study E5194

711 women enrolled 1997 to 2002
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Grade 1 or 2 DCIS, ≤ 2.5 cm:
Grade 3 DCIS, ≤ 1 cm:
Ineligible:

580 pts
102 pts
29 pts
Mean age of eligible patients is 60 years
 31% declared intent to take Tam
 Median f/u 4.96 years
 Post excision mammogram for residual
microcalcifications, central path review
*ECOG, NCCTG
Abstract 29, Intergroup* Study E5194

Principle Outcome Measures
Low or intermediate grade DCIS
High grade DCIS
N, mean age 60 (range 28 – 88)
580
102
Median size
6 mm (only 18% > 1 cm)
7 mm
Median margin width
5 to 10 mm
5 to 10 mm
IBTR at 5 years
6.8%
13.7%
IBTR DCIS
50%
50%
IBTR Invasive
53%
47%
Absolute IBTR Invasive
≈ 3.6%
≈ 6.4% (B-17/RT 3.9% 8 years)
Contralateral breast events at 5 years
3.5%
4.2%

Conclusions
– Low to intermediate grade DCIS has low recurrence rate w/o RT
– High grade DCIS has a high recurrence rate suggesting surgery alone is
inadequate
Abstract 29, Intergroup* Study E5194

Is this real?
– Dana Farber data demonstrates higher
recurrence rates without RT, IBTR 12% at 5
years, with low/intermediate grade and margins
> 1 cm (TAM not allowed)
– Van Nuys data demonstrates low recurrence
rates overall if margins > 1 cm, IBTR 13.9%,
invasive IBTR 3.4% at 12 years

higher recurrence rates with grade 3 DCIS
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J Clin Oncol (United States), Mar 1 2006, 24(7) p1031-6

Am J Surg (United States), Oct 2006, 192(4) p420-2
Abstract 29, Intergroup* Study E5194
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Where does one go from here?
– RTOG 98-04 randomized study closed to
accrual, results pending
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Favorable DCIS +/- Tam +/- RT
–
–
–
–
–
Low to intermediate grade
3-9 mm margins vs 1 cm or greater
< 1 cm lesion vs 1 to 2.5 cm
Age < or > 50
TAM yes vs no
Sentinel Node Biopsy
ITC (Nanomets) and Micromets
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Abstract 25, Axillary Lymph Node ITC
(Nanometastases) are Prognostic Factors for
Metastatic Relapse. “These results support the
inclusion of procedures for nanometastasis
detection in TNM pathologic staging.”
– National Cancer Institute, Milan, Italy
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Plenary session, 3, Micrometastases in the
Sentinel Node “One should not look too hard for
micrometastases in the sentinel node.”
– The Netherlands Cancer Institute, Amsterdam,
Netherlands
Abstract 25, Sentinel Node Biopsy
ITC (Nanomets)

Compared with standard H&E staining
– step sectioning increases sensitivity 10%
– IHC increases sensitivity 10% further
– RT-PCT increases sensitivity 10 further still
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What is the value of these observations?
– Are these metastatic “cells” viable?
– Are these simply displaced cells?
Abstract 25, Sentinel Node Biopsy
ITC (Nanomets)
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Abstract 25, Axillary Lymph Node ITC (Nanometastases) are
Prognostic Factors
702 consecutive patients at the National Cancer Institute, Milan
– pN0
– Completion axillary dissections
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8 years median f/u
Outcomes
– Risk of first adverse event
 Crude cumulative incidence curves generated to estimate cumulative
probability of occurrence of adverse events
– Distant relapse
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pN0(i+) is a strong risk factor for event free survival (p<.0005) and for
metastatic relapse in both univariate and multivariate analysis
accounting for grading, T stage, and age
Plenary Session 3, Sentinel Node Biopsy
Micromets
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Meta-analysis of 25 studies, > 8,687 published patients who had neg SN bx
–
3 years mean f/u
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31 relapses, axillary recurrence only .36% (.8% to 2.3% reported for ALND)
Compare this with false negative rate after upfront ALND, which ranges from 2 to 11% in
the literature
Conclusion: not all histologic findings of residual disease represent viable tumor
–
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What does this mean for micrometastases?
–
Should they be ignored?
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Iatrogenic tumor cell displacement recognized, papillary lesions, DCIS (Bleiweiss JCO, 2006)
Can micrometastases predict non-SN metastasis, whether additional micrometastases or
macrometastases?
Prognostically, may not add much information above and beyond tumor size and grade
Conclusions
–
–
–
ITC can be ignored
Micrometastases should be treated with completion ALND or systemic therapy
If completion ALND, and other nodes are negative, treatment should be based on
the characteristics of the primary tumor, not the presence of the micrometastasis
Sentinel Node Biopsy
Micromets
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Are these findings real?
– Are nanometastases prognostic?
– Should micrometastases be ignored?
Sentinel Node Biopsy
Significance of ITC and Micromets
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Where does one go from here?
Data from randomized studies pending
– NSABP B-32
– ACOSOG Z10
– IBCSG 230-1: focused specifically on micromets
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New randomized studies incorporate gene signature
patterns as prognostic tools
– Trial Assigning IndividuaLized Options for Treatment (Rx), or
TAILORx
– MINDACT (MIcroarray for Node negative Disease may Avoid
ChemoTherapy).
– Will micrometastases be as/more/less prognostic than a gene
signature?
Intraoperative SN Evaluation
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Abstract 26, Sentinel Node Biopsy in
Invasive Ductal Carcinoma, Invasive
Lobular Carcinoma, Favorable Histologic
Subtypes
 Abstract 28, Multiplex Molecular Assay
Has Improved Sensitivity over Histologic
Intraoperative Nodal Metastases Tests
Abstract 26
Sentinel Node Biopsy in IDC, ILC, and
Favorable Subtypes
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Single institution, 5,298 consecutive patients with T1-3 invasive
carcinoma, 1996 to 2004
SLN bx with frozen section (FS)
IDC
ILC
Frozen Section (FS) Sensitivity 62%
52%
p=.006
46%
Yield (% pos SN Bx)
21%
p=.487
3%
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22%
Favorable
p=<0.001
For IDC and ILC, but not Fav, yield increased with Tumor Size
Sensitivity and yield of FS were higher with patients < 50, increasing
tumor size, and AL invasion.
Yield of FS was < 10% for all patients with ID/IL tumors < 1 cm in size
who were older than age 60.
Abstract 26
Sentinel Node Biopsy in IDC, ILC, and
Favorable Subtypes
 Conclusion: for ID and IL, overall
sensitivity is > 50%
 For any individual with age > 60, T1a or b
tumor of any histology, yield < 10%
– Intraoperative FS is not worthwhile for this low
yield subset.
Abstract 28, Multiplex Molecular Assay

Standard H&E processing of axillary node
samples 2 to 5%, and will miss 10 to 15%
of nodal metastases
 Intraoperative evaluation even less sensitive
Abstract 28, Multiplex Molecular Assay
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RT-PCR kit for intraoperative SN evaluation
– GeneSearch™ BLN Assay
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Markers
– Mammoglobin (breast)
– Cytokeratin 19 (epithelial)
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Closed tube system
If either or both are “positive”, node is “positive”
– Approximately ½ hour to perform test
– Does not require a pathologist
– Price not set
Abstract 28, Multiplex Molecular Assay
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RT-PCR kit for intraoperative SN evaluation
– Approximately 1,000 cells in a .2 mm micromet
– Assay designed to report < 1,000 cells as “negative”
– Therefore, will detect metastases > .2 mm and give a
“positive” result
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Clinical trial design
– Half of lymph node sent for standard SN processing
– Half of lymph node sent for RT-PCR
Abstract 28, Multiplex Molecular Assay
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FS used at 11 sites testing 319 patients
 TP used for 29 subjects
Pts
FS
BLN Asay
Overall
Sensitivity
Sensitivi
ty for
ILC
Sensiviti
ty for
tumor >
2 mm in
size
Sensitivi
ty for
microme
ts
Specifici
cty
85.60%
65.2%
90.8%
54.5%
97.8%
4.4%
95.6%
91.3%
100%
81.8%
94.3%
54.5%
45.5%
57.1%
25.0%
100%
36.4%
63.6%
100%
0%
100%
319 14.4%
BLN Assay
TP
Overall
FN rate
29
Abstract 28, Multiplex Molecular Assay
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Are these results real?
– RT-PCR has been used for evaluation of axillary nodes
previously, not novel
– Prior difficulty has been false positive findings and
complexity of performing assay in “real time”
– Addition of “real time” evaluation of nodal material, and
quantitative assessment of RT-PCR findings is novel
– No other publications for direct comparison
Abstract 28, Multiplex Molecular Assay
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Where do we go from here?
– Additional data forthcoming from company regarding
cost
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Weigh cost of assay versus cost of return trip to OR for
completion ALND
Long term
– Where will SNB fit compared to gene signature assays,
such as Mammaprint, Oncotype DX?
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Will SNB become obsolete?
Abstract 27, The RACS/SNAC Trial
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32 Sites in Australia/New Zealand
– SNB + ALND (RAC), 544 patients
– SNB +/- Delayed ALND if SN + (SNBM), 544 patients
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Surgeon accreditation required
– Lymphoscintigraphy and blue dye
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Outcomes measures
– To assess performance of SNB
– To assess morbidity of SNB vs ALND in first 12 mos
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Subjective symptoms
Objective findings
Complication rates
Abstract 27, The RACS/SNAC Trial
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Patient characteristics
– 1,088 patients
– Mean age 60
– Identification
 Screening 58%
– Mean tumor size 1.6 cm
– Breast conservation 87%
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Mapping technique
– Tracer 89%
– Blue dye 99%
 Blue dye alone 11%
– Mean number of SN, 1.7 nodes
– Mean number of SN in RAC 14.6 nodes +/- 7
Abstract 27, The RACS/SNAC Trial
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Results
– SNB performance
SN
SN +/Not
found
SN only Sensitivity,
+ node FN rate
SNBM 4%
29%/67% 63%
RAC
25%/69%
7%
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92%, 8%
Proportion with All subj sx
Complications
> 15% inc arm 0 to 100 (worst) Seroma
vol (p=.05)
(p < .001)
4.2%
4.3
93
7.1%
7
195
Conclusions
– SNB is accurate
– SNB has lower morbidity
 Should dysfunction in SNBM group decreased over time
 Arm swelling in RCA group increased over time
Abstract 27, The RACS/SNAC Trial

Are these findings real?
– SB accuracy rate comparable to that seen in other
randomized trials
– Lymphedema rate for SNB alone arm higher than
originally expected, but lower than that seen in other
trials
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NSABP B32
Z10
Almanac
Abstract 27, The RACS/SNAC Trial
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Where does one go from here?
– SNB alone remains attractive from a quality of life
perspective
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Still SNB alone is not without significant symptoms
– Is SNB oncologically safe?
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Survival data lacking from this study
Question remains unanswered
– NSABP B32 pending
– Z10 pending
CALGB Study C9343 Update
Clinical T1N0, ER +, age ≥ 70
 636 women enrolled 1994 to 1999

– Tam RT 317
– Tam No RT 319
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Previous report 5 year f/u
 Current update 7.9 year f/u
CALGB Study C9343 Update

Principle Outcome Measures
– IBTR
– Frequency of mastectomy
– Time to distant metastases
– Breast cancer specific mortality
– All cause mortality
CALGB Study C9343 Update

Principle Outcome Measures
Tam + RT
Tam
Breast
Axilla
Breast
Axilla
IBTR
3 (1%)
0
20 (6.3%)
4
Mastectomy
3 (1%)
9 (3%)
p = .07
Time to DM
9 (3%)
11 (3%)
p = .59
Breast Cancer Specific Mortality
5 (2%)
5 (2%)
p = .92
All Cause Mortality
82 (26%)
86 (27%)
p = .84

(p < .001)
Conclusions
– WB-XRT reduces IBTR 5.3% for women ≥ 70, clinical T1N0, ER pos
– WB-XRT reduction in mastectomy 1% vs 3%, p=NS at 7.9 years f/u
– Breast cancer specific mortality identical at 2% at 7.9 years f/u
– All cause mortality ≈ 26% for both w or w/o RT at 7.9 years f/u
CALGB Study C9343 Update
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Is this real? Probably so.
– NSABP B-21
– Fyles subset analysis
– Milan III
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This study just proves point
– IBTR is less likely as patients age
CALGB Study C9343 Update
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Where does one go from here?
 Arimidex replacing Tamoxifen
– Arim reduces IBTR compared with Tam
– Arim alone even more compelling in women ≥ 70

However, APBI will replace WB-XRT
– APBI easier on patients, better tolerated, than WB-XRT
– Will effectiveness of lower morbidity of APBI diminish
arguments against WB-XRT in terms of time, cost,
complications?

NSABP B39 in progress