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2. disease
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Updates in Breast Cancer Care
Dr. Courtney A. Vito, MD, FACS
Assistant Clinical Professor of Surgcal Oncology
City of Hope National Medical Center
12/8/2014
Disclosures
• No relevant financial
disclosures
• Serve as PI for the
Xoft/i-Cad Med
sponsored IORT trial
at City of Hope
Standard Treatment of Breast Cancer
Surgical Intervention
Lumpectomy or Mastectomy
SLN Bx +/- ALND
Systemic Medical Therapy
Chemotherapy +/- Antihormonal therapy
Antihormonal therpay
Radiation Therapy
Whole breast XRT after all lumpectomies
WB XRT for ≥N2 (with nodal fields) or ≥T3
after mastectomy
Breast Surgery
Major Changes in Surgical
Management-Breast
• Oncoplastic surgery-Partial resection of the
breast including areas involved by tumor(s)
and repackaging of the residual tissue into an
improved breast form
• Nipple sparing mastectomy-The removal of
essentially all breast tissue with preservation
of the entire skin envelope including the
nipple-areolar complex
Breast Conservation
• Validated in landmark trial NSABP B06
– Mastectomy not necessary in early T stage,
unifocal breast cancer (T1, T2).
– Nodal status does not dictate breast procedure
– Slightly higher in breast recurrence rates with
lumpectomy/XRT compared with mastectomy but
survival remains unaffected
In Breast Recurrence Patterns
• 93% of all ipsilateral inbreast recurrences after
BCT occurred within the
same quadrant
• 95% were histologically
the same or similar
tumors
* Average follow-up 103 mos.
Fisher ER, Anderson S, Redmond C, Fisher B. Ipsilateral breast tumor recurrence and survival following lumpectomy
and irradiation: pathological findings from NSABP protocol B-06 Semin Surg Oncol. 1992 May-Jun;8(3):161-6
Oncoplastic Surgery
• Allows you to push the envelope with
multifocal tumors and breast conservation
(multicentric also possible but remains
controversial)
• Improves cosmetic outcome
• Allows for wider margins in many cases*
• Improved sexual function of the breast
• Decrease surgical burden for pt when
mastectomy/reconstruction are avoided
Benefits of Oncoplasty-Meta-Analysis
Oncoplasty
(n=3165, 41 ref)
Lumpectomy Alone
(N=5494, 20 ref)
P-Value
Tumor size
2.7 cm
1.2 cm
Rate of Positive
Margin
12%
21%
<0.0001
Rate of Re-excision
4%
14.6%
<0.0001
Conversion to
mastectomy
65%
3.8%
<0.0001
Recurrence rate*
4%
7%
<0.0001
Satisfaction w
cosmesis
89.5%
82.9%
<0.001
*ave follow up 37 mos oncoplasty vs. 64 lumpectomy
Losken A et al. “A meta-analysis comparing breast conservation therapy alone to the oncoplastic technique.” Ann Plast Surg 2014
Feb;72(2):145-9.
Mastectomy vs. Oncoplasty
Mastectomy w immediate
recon (n=60)
Oncoplastic breast
conservation (n=10)
Satisfaction w sex life 1 yr ∆ NS
NS
Satisfaction w body image
1 yr ∆
3.37 to 3.44 NS
2.80 to 3.80 (Intergroup
p=0.03)
Pursuit of sexual
attractiveness 1 yr ∆
3.78 to 3.31 (p=0.02)
NS
Expected improvement in
body image w surgery
3.89 to 3.33 (p=<0.01)
3.60 to 4.00 (NS but
intergroup p=0.02)
Increase in partner’s
perception of woman 1yr
NS
1.33 to 2.50 (p=0.01)
Ability to wear provocative
clothing
NS
1.78 to 3.11 (p=<0.01)
Hart A, Pinell-White X et al “The psychosexual impact of partial and total breast reconstruction: A prospective 1-year
longitudinal study. Ann of Plas Surg. e pub. 10 Apr 2104
Hallmarks of oncoplastic approach
1. Consider the skin a drape to mask underlying
work. Consider it separately from the
underlying gland. Undermining the skin is
always the first step.
Clough KB Ann Surg Oncol (2010)
17:1375-91
Hallmarks of oncoplastic approach
2. Full thickness excision of the gland (+/undermining NAC). THEN…continue to
undermine flaps off of the pectoralis muscle for
mobility.
Clough KB Ann Surg Oncol (2010) 17:1375-91
Hallmarks of oncoplastic approach
• Reshape the gland
with multilayer
closure of
advancement flaps
• Close at least 3
layers, including cut
fascial edges
Clough KB Ann Surg Oncol (2010) 17:1375-91
Hallmarks of oncoplastic approach
• Reposition the
NAC as necessary
Clough KB Ann Surg Oncol (2010) 17:1375-91
X
X
Is oncoplasty REALLY that important??
YES!!!!!
Mastectomy Trends
• Preservation of skin envelope
• Rise in contralateral prophylactic mastectomy
• Improvement in reconstructive techniques
Conventional Mastectomy
Mastectomy with Reconstruction
Nipple Sparing Mastectomy
Safety of Nipple Sparing Mastectomy
Wang F, Peled AW, Garwood
E, Fiscalini AS, Sbitany H,
Foster RD, Alvarado M,
Ewing C, Hwang ES,
Esserman LJ. Total skinsparing mastectomy and
immediate breast
reconstruction: an evolution
of technique and
assessment of outcomes.
Ann Surg Oncol. 2014
Oct;21(10):3223-30.
Shhhhh, the #1 Secret in Breast
Surgery is……
It’s All About the Axilla
Axillary Surgery
Major Changes in Surgical
Management of the Axilla
• Less rigor is employed in clinical assessment of
axillary nodal status
• A single positive sentinel node no longer
triggers completion axillary dissection!
• Less complete axillary staging does not seem
to affect survival or locoregional recurrence as
best we now know.
• Stage migration over the long term is a
possibility
NSABP B04
ACOSOG Z0011
Inclusion/Exclusion
• Inclusion
– cT1-2 N0 M0 women undergoing BCT and SLN bx
– + SLN on frozen, touch-prep, routine H&E (not IHC)
• Exclusion
–
–
–
–
–
Clinically positive nodes (US included*)
3 or more + SLN
Matted nodes or gross extranodal extension
Mastectomy
Any form of neoadjuvant therapy
From: Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node
Metastasis: A Randomized Clinical Trial
JAMA. 2011;305(6):569-575. doi:10.1001/jama.2011.90
Figure Legend:
ALND indicates axillary lymph node dissection; SLND, sentinel lymph node dissection.
Date of download: 10/13/2013
Copyright © 2012 American Medical
Association. All rights reserved.
From: Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node
Metastasis: A Randomized Clinical Trial
JAMA. 2011;305(6):569-575. doi:10.1001/jama.2011.90
Figure Legend:
ALND indicates axillary lymph node dissection; SLND, sentinel lymph node dissection.
Copyright © 2012 American Medical
Association. All rights reserved.
From: Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node
Metastasis: A Randomized Clinical Trial
JAMA. 2011;305(6):569-575. doi:10.1001/jama.2011.90
Figure Legend:
Blue dashed line at hazard ratio = 1.3 indicates noninferiority margin; blue-tinted region to the left of hazard ratio = 1.3 indicates
values for which SLND alone would be considered noninferior to SLND plus ALND. ALND indicates axillary lymph node dissection;
CI, confidence interval; SLND, sentinel lymph node dissection.
Date of download: 10/21/2013
Copyright © 2012 American Medical
Association. All rights reserved.
Lessons Learned
• Practice changing trial with new guidelines
rapidly accepted by multiple professional
societies
• Currently, for any patient undergoing primary
surgery in form of BCT, ALND is only standard
of care for 3 or more positive SLN
• Calls into question necessary extent of presurgical LN evaluation
AMAROS Trial
• Clinically node negative women with tumors up
to 5 cm in size (expanded from 3 cm)
• Essentially studied same group as ACOSOG Z0011
but key difference is that mastectomy patients
were included and that treatment arm included
dedicated axillary field radiation
• Groups were randomized to ALND or radiation
after positive SLN bx
• Patients were followed for OS, LRR and
lymphedema development
Straver M E et al. JCO 2010;28:731-737
Conclusions and Confusions
• Both ACOSOG Z0011 and AMAROS support the
avoidance of ALND in clinically node negative
women with small amount of pathologic nodal
involvement
• Axillary recurrence remains rare whether patients
receive axillary radiation (AMAROS) or not
(Z0011) pts. For whom then is axillary radiation
necessary?
– There may be a subset of patients who benefits, but
further study is needed
Axillary Management After
Neoadjuvant Chemotherapy
• Sentinel lymph node biopsy is now widely
accepted for pts who had a clinically node
negative axilla prior to starting chemotherapy
• Routine ALND is reserved for those with
positive SLN bx or clinically positive axilla
initially
• The downstaged axilla post-NCT is an area of
hot debate
ACOSOG 1071
• Accrued 756 patients with core-needle bx proven
axillary metastases who then underwent
neoadjuvant chemotherapy
• Post-chemotherapy, all patients were subjected
to SLN bx with mandatory completion axillary
dissection
• Goal of trial was to prove feasibility in identifying
SLN after chemotherapy and its accuracy in
predicting residual disease in the axilla
Results
• Overall 91.2% SLN bx correctly identified axillary status
• 40% of patients had a nodal pCR
• 12.6% overall false negative rate of SLN bx when 2 or
more SLNs were found (FN rate 31.5% if only 1 SLN
found)
• FN rate decreased 9.1% if 3 or more SLN ID
• FN rate further decreased to 10.8% if pathologist could
ID evidence of chemo effect in nodes regardless of
number harvested
• FN decreased to 7.4% if node was clipped at CNbx as
found in SLN specimen regardless of number of nodes;
14% FN if no clipping was done
Rates of ID SLN
• 88.9% rate of SLN ID with 1 tracer, but 93.8%
rate of ID when dual tracer was used
– 22.2% FN rate with blue dye alone
– 20% FN rate with technetium alone
– 10.8% FN rate with dual tracer
Authors’ Conclusion
• Trial set a goal of no more than 10% overall FN
rate, and though this was not achieved
(12.8%), it was in certain subsets and merits
further study
SENTINA Trial
cN0
cN1
SLN Bx
NCT
pN0
pN1
NCT
No further
axillary surgery
ARM A
ycN0
ycN1
SLN Bx +
ALND ARM C
ALND alone
ARM D
NCT
SLN Bx + ALND
ARM B
SLN Detected and Removed
P=<0.001
P=<0.001
P=<0.001
99.1%
(1013/1022)
60.8%
(474/592)
SLN Bx prior to any
NCT
Re SLN Bx after
SLN Bx + NCT+
ycN0
80.1%
(219/360)
Primary SLN bx
after NCT=ycN0
False Negative Rate SLN Bx after
NCT
ypN 0: 155
(70.8%) ypN 1: 64
(29.2%)
ypN 0: 248
(52.3%) ypN 1:
226 (47.7%)
95 % CI 38.7% - 64.2 %
95 % CI 9.9% – 19.4%
33 / 64
32 / 226
Authors’ Conclusions
• The Detection Rate (DR) for the SLN is excellent
for patients who receive SLNB prior to systemic
treatment
• Repeated SLNBx is associated with an
unacceptable DR Patients who convert under
NACT from cN1 to ycN0 have a DR of only 80.1 %
• The FNR for patients, who are downstaged
through NACT from a positive to a negative
axillary status appears less favourable compared
to the FNR in patients who undergo primary
surgery
Recommendations
• Pre-neoadjuvant SLN bx should be used only in
rare circumstances, and post-neoadjuvant SLN bx
should not be attempted
• Dual tracer should always be used
• ID of fewer than 2 LNs should be considered a
mapping failure and completion ALND performed
• Clip should be placed into nodes at bx if pt is
undergoing neoadjuvant chemo and should be
ID’ed in SLN. If not ID’ed, do we consider this a
mapping failure with need for cALND?
Alliance A 11202 Schema
CNBx proves + mets
NACT followed by
surgery with SLN Bx
Node Positive
Node Negative
No further surgery;
Rec enrollment in
NRG 9355
XRT alone
ALND + XRT
NRG 9353 (NSABP B51)
Post-neoadjuvant
SLN bx negative after
previously + on CNBx
No axillary field XRT;
No chest wall XRT if
mastectomy, but
breast XRT if BCT
Whole breast or
chest wall XRT with
additional axillary
fields
Radiation
Use of Radiation
• Well validated for use to treat the breast after
lumpectomy for locoregional control
• Well validated to improve locoregional control
when fields are expanded to cover nodal
basins with 4 or more nodes involved
• Extent of fields needed after 1-3 positive SLN
is controversial, especially after mastectomy
But in the node negative…
• Hughes data indicates diminishing return on
radiation after lumpectomy in older age
groups
• Newer data indicates that whole breast
radiation may not be necessary
• Intraoperative radiation therapy is becoming a
more viable option of those with early stage
breast cancer undergoing breast conservation
therapy
What is Intra-Operative Radiation
Therapy
• IORT is the delivery of a single dose of
targeted radiation to the lumpectomy bed at
the time of surgery
– 3 devices currently employed, 2 of which have
data from large, multi-center, randomized
controlled trials
– Treats 1 cm around the cavity
– Done in place of whole breast radiation in most
cases
2009 ASTRO Guidelines for APBI
Candidates
Suitable
Cautionary
Unsuitable
Definition
Off Clinical Trial
Limited Data
On Trial Only
Age
≥60
50-60
<50
T-size
≤2cm
2-3cm
>3cm or inflammatory
Nodes
Negative
---
Positive or not evaled
Histology
IDCA
ILCA, DCIS
---
Margins
>2mm
≤2mm
positive
Path Features
No EIC nor LVI
EIC or Focal LVI
Extensive LVI
Grade
Any
---
Multicentricity
Clinically unifocal
---
Any multifocality/centricity
ER status
Positive
Negative
---
Neoadjuvant Tx
None
---
If any used
BRCA Status
Negative
---
Positive or suspected
ELIOT: A Randomised Controlled
Equivalence Trial
• 1305 pts were randomized to treatment with
intra-operative electron therapy (ELIOT) or
WBRT after quadrantectomy
• Eligibility criteria for treatment was female
sex, age 48-75, unifocal tumor, tumor size <2.5
cm by pre-operative imaging
Veronesi U, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a
randomized controlled equivalence trial. Lancet Oncol. 2013;14:1269–77.
ELIOT Operative Procedure
ELIOT Trial Radiation Technique
Results
Veronesi U, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomized
controlled equivalence trial. Lancet Oncol. 2013;14:1269–77.
Overall and Breast Cancer-Specific Survival of
Patients Treated with IORT
Veronesi U, et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with
electrons. Breast Ca Res Treat. 124: 141-151.
WBRT at 50Gy + Boost vs. ELIOT at
21 Gy
Veronesi U, et al. Intraoperative radiotherapy during breast conserving surgery: a study on
1,822 cases treated with electrons. Breast Ca Res Treat. 124: 141-151.
Final Analysis of Outcome
• Statistically less skin damage and pulmonary toxicity IORT vs.
WBRT (Veronesi 2013)
• >10% local recurrences at 5 yrs in IORT patients who had:
–
–
–
–
>2 cm tumors
4 or more positive nodes
ER-negative tumors
Poorly differentiated histology
• Overall survival is equivalent
Silverstein MJ, Fastner G, Maluta S, Reitsamer , Goer DA, Vicini F, Wazer D. Intraoperative Radiation Therapy: A Critical
Analysis of the ELIOT and TARGIT Trials. Part 1-ELIOT. Ann Surg Oncol. 2014 Nov;21(12):3787-92
ELIOT Trial Subjects per ASTRO Guidelines
Suitable
Cautionary
Unsuitable
Definition
Off Clinical Trial
Limited Data
On Trial Only
Age
≥60 50%
50-60 44%
<50 7%
T-size
≤2cm 88%
2-3cm
>3cm or inflammatory
Nodes
Negative 74%
---
Positive/not evaled 26%
Histology
IDCA 81%
ILCA, DCIS 19%*
---
Margins
>2mm
≤2mm
positive
Path Features
No EIC nor LVI
EIC or Focal LVI
Extensive LVI
Grade
Any
---
Multicentricity
Clinically unifocal
---
Any multifocality/centricity
ER status
Positive 90%
Negative 10%
---
Neoadjuvant Tx
None
---
If any used
BRCA Status
Negative
---
Positive or suspected
* 11% lobular or mixed, 8% other unspecified
TARGIT-A Trial
•
•
2232 patients undergoing breast
conservation randomized to IORT via
xray source (Zeiss Intrabeam) vs.
WBRT
Eligible pts
–
–
–
–
–
–
•
Age >=45
Pathology documented invasive ductal cancer
Suitable for breast conserving surgery
Tumor clinically <=2.5 cm
No contraindication for breast irradiation
ECOG 0-2
Non-inferiority trial (2.5% local
recurrence)
Vaidya JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international,
prospective, randomised, non-inferiority phase 3 trial. Lancet. 2010;376(9735):91-102
Patient Characteristics
Vaidya JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A
trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet. 2010;376(9735):91-102
TARGIT-A
2014 Updated TARGIT-A Data
*Only group to
breach non-inferiority
benchmark
Kaplan-Meier analysis of
local recurrence in the
conserved breast and death
for the two strata as per
timing of randomisation and
delivery of TARGIT
(prepathology vs
postpathology) Local
recurrence was the primary
outcome, death was a
secondary.
Vadiya JS, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5year results for local control and overall survival from the TARGIT-A randomised trial The Lancet, Volume 383, Issue 9917,
2014, 603 – 613. http://dx.doi.org/10.1016/S0140-6736(13)61950-9
2014 Updated TARGIT-A Data
Kaplan-Meier analysis of breast cancer deaths and non-breast-cancer deaths (A) Breast cancer. (B) Non-breast-cancer. TARGIT=targeted
intraoperative radiotherapy. EBRT=external beam radiotherapy.
Vaidya JS et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5year results for local control and overall survival from the TARGIT-A randomised trial. The Lancet, Volume 383, Issue 9917,
2014, 603 – 613. http://dx.doi.org/10.1016/S0140-6736(13)61950-9
TARGIT-A Subjects per ASTRO Guidelines
Suitable
Cautionary
Unsuitable
Definition
Off Clinical Trial
Limited Data
On Trial Only
Age
≥60
50-60
<50
T-size
≤2cm
2-3cm
>3cm or inflammatory
Nodes
Negative
---
Positive or not evaled
Histology
IDCA
ILCA, DCIS
---
Margins
>2mm
≤2mm
positive
Path Features
No EIC nor LVI
EIC or Focal LVI
Extensive LVI
Grade
Any
---
Multicentricity
Clinically unifocal
---
Any multifocality/centricity
ER status
Positive
Negative
---
Neoadjuvant Tx
None
---
If any used
BRCA Status
Negative
---
Positive or suspected
TARGIT-A
708 (32%)
613 (27%)
911 (41%)
Benefits of IORT…
• PATIENT CONVENIENCE
– All local treatment accomplished in OR vs.
multiple trips to radiation treatment center
and/or caring for external catheter
– Local skin effects are virtually none barring
technical error
– Enables us to offer breast conservation to patients
who might otherwise choose mastectomy
Benefits of IORT…
• COSMETIC BENEFIT
– Oncoplastic surgery possible after IORT unlike
other catheter-based APBI
– Little to no risk of capsular contracture with
existing implants
– Retain low-risk implant-based reconstruction
options in case of recurrence
– Decreased risk of breast asymmetry
In Conclusion…
• WBRT is still the gold standard, and we are still learning who
the best candidates for IORT may be
• OS is not affected by method of radiation and overall the IBRT,
though higher with IORT, is still relatively uncommon
• IORT confers many benefits that WBRT does not
• Patients must be highly selected with strong consideration for
treatment to be given on-protocol. Any patient undergoing
IORT should receive close follow up monitoring
• IORT should be done at the time of initial lumpectomy
• Further investigation is merited
THANK YOU