Risk Reducing Mastectomy:
Indications and Results
Kelly K. Hunt, M.D.
Department of Breast Surgical
Oncology
Outline
• Identification of high-risk patients
• Efficacy of BPM
• Contralateral breast cancer
• Efficacy of CPM
• Nipple sparing mastectomy
Breast Cancer Risk Assessment
• Detailed personal and family history
• If no significant family history: Gail Model
✓Age
✓Age at menarche
✓Age at first live birth
✓Family history
✓History of previous biopsies and of ADH
✓Race
• Risk reduction counseling if modified Gail risk 5 yr >1.7% and life expectancy >10 yr
Risk Assessment in Patients
with Family History
• If family history
• Claus model
• Genetic counseling
• BRCA Status Prediction Models (eg
BRCAPRO, Myriad)
• Genetic testing
Genetic Testing
• Indications for genetic testing
• Patient factors
• Young age at presentation
• Triple negative disease
• Family history
• Number of female relatives with cancer
• Age at diagnosis
• Male breast cancer/ovarian cancer
• Paternal side as important as maternal
Breast Cancer Etiology
Filippini et al Front Bio 2013
Genetic Testing
• High penetrance – high risk (50% or greater)
• BRCA1 and BRCA2 (50-85%), PALB2 (33-58%),
TP53 (50-90%) , PTEN (25-50%), STK11 (32-54%),
CDH1 (30-50%)
• Moderate penetrance – moderate risk (20 to 49%)
• CHEK2 (20-40%), ATM (20%), NBN (20-30%)
• Low penetrance – lower risk
• BRIP1 (20%)
• MRE11A, RAD50
Krontiras et al. Surg Clin N Am 2018
BRCA Mutation Carriers
• Surgical options for the breast
• Bilateral prophylactic mastectomy (BPM) -
decreases risk of breast cancer by 90-95%
• Hormonal risk reduction options
• Bilateral salpingo-oophorectomy (BSO)
• Decreases risk of breast cancer by 50%
• Decreased risk of ovarian cancer by 90%
• Screening
• Annual mammography and MRI
• Clinical exam Q6 months
• Ca-125 and pelvic ultrasound for BRCA carriers
Efficacy of Prophylactic
Mastectomy
• Several reports of breast cancer
development following prophylactic
mastectomy
• PM is “risk-reducing”, not 100%
prophylactic
Efficacy of BPM
• 639 BPM at Mayo Clinic 1960-1993, 90%
subcutaneous mastectomy
• Follow-up 14 years
• 214 high risk patients:
– Compared with their sisters: 3 of 214 probands
(1.4%) developed BC, compared with 156 of 403
(38.7%): RR >90%
• 425 moderate risk patients:
– Based on Gail model, 37.4 BC expected, 4
occurred: RR 89.5%
Hartmann LC et al, N Engl J Med, 1999
Risk Reduction
• Prophylactic mastectomy reduces
risk of developing breast cancer by
90+%
* 90% is the relative risk reduction, not
absolute benefit
Relative vs Absolute Risk Reduction
• Lifetime risk of breast cancer 100%
– After RR mastectomy, reduce risk to <10%
– In this case absolute benefit and relative
benefit are same: 90%
• Lifetime risk of breast cancer 10%
– After RR mastectomy, reduce risk to 1%
– Relative benefit is 90%, absolute benefit is 9%
Benefit of BPM
Risk and
Outcome*
Outcome
Rate
without
Mastectomy
Outcome
Rate with
Mastectomy
Absolute
Risk
Reduction
Relative
Risk
Reduction
Number
Needed
to Treat
High
Breast cancer
Death
Moderate
Breast cancer
Death
0.175
0.049
0.088
0.024
0.014
0.009
0.009
0.000
0.161
0.040
0.079
0.024
0.920
0.816
0.898
1.000
6
25
13
42
*On the basis of the data reported by Hartmann et al.
Hamm, et al. NEJM, 1999
The higher the absolute risk, the greater the benefit derived
BPM for BRCA Mutation Carriers
PO
44 patients (58%)
76 patients
PM
average age 37.7yrs
PO
24 patients (38%)
63 patients
surveillance
average age 39.5yrs
139 patients
Meijers-Heijboer et al. N Engl J Med, 2001
Median follow-up: 2.9 years
BPM for BRCA Mutation Carriers
Meijers-Heijboer, et al. N Engl J Med, 2001
BPM for BRCA Mutation Carriers
2 patients with
breast cancer
105 patients
PM
184 patients with
breast cancer
378 patients
surveillance
483 patients
PROSE Group Study, J Clin Oncol, 2004
Mean follow-up: 6.4 years
BPM for BRCA Mutation Carriers
PROSE Group Study, J Clin Oncol, 2004
BPM for BRCA Mutation Carriers
* In BRCA 1/2 mutation carriers
> Bilateral PM reduces the risk for
developing breast cancer by 90%
> Absolute risk reduction 46.8%
* Survival endpoints not evaluated
PROSE Group Study, J Clin Oncol, 2004
Risk-Reducing Surgery
• 2482 women with BRCA 1 or 2 mutations,
enrolled 1974-2008
• 247 mastectomies – no breast cancer vs 98
women with breast cancer who did not have PM
• Salpingo-oophorectomy – associated with
improved ovarian cancer and breast and cancer
outcomes
• Salpingo-oophorectomy also resulted in lower all
cause mortality, improved breast cancer-specific
mortality and ovarian cancer specific mortality
Domchek SM, et al. JAMA 2010
Risk of Contralateral Breast Cancer
• Overall risk varies between 0.13%-1.4% per
year
– In BRCA patients: 3-5%/year
– In patients with strong FH: 2.1%/year
• Risk remains constant over time
– Unlike systemic recurrence which is greatest 1-2
years after completion of treatment
• Most studies demonstrate contralateral breast
cancer diagnosed at an earlier stage
Contralateral Breast Cancer BRCA 1/2 mutation
• 491 women with BRCA1 or 2 and stage 1 or 2
breast cancer
• Actual risk of CBC 29.5% at 10 years
• Reduced risk:
– BRCA2 HR 0.75
– >50 years HR 0.63
– Use of tamoxifen HR 0.59
– Oophorectomy HR 0.44
• 10 yr risk of CBC if no tamoxifen or oophorectomy
is 43.4% BRCA1 and 34.6% BRCA2
Metcalfe K, J Clin Oncol, 2004:22:2328-2335
CBC risk in BRCA mutation carriers by
age of first cancer diagnosis
N= 2020, Graeser et al., J Clin Oncol 2009
CPM and Survival in BRCA Mutation Carriers
Metcalfe et al., BMJ, 2014
• 390 patients (180 had CPM) median follow-
up 14.3 yrs
• 20 yr survival rate for CPM 88% vs 66%
• Multivariable analysis, controlling for age at
diagnosis, treatment, and other prognostic
features, contralateral mastectomy was
associated with a 48% reduction in death
from breast cancer; P =0.03
Mastectomy Techniqes
• Subcutaneous mastectomy
– Woods, Mayo Clinic
– A “1 cm thick button of tissue” left
beneath the areola to preserve the blood
supply, Ann Plast Surg 1987
• Skin-sparing mastectomy
– Flaps raised between the plane of the
breast and the subcutaneous tissue
• Nipple-sparing mastectomy
– Coring of the nipple ducts?
Concerns about Nipple-Areolar
Preservation
• In the setting of invasive or non-
invasive breast cancer:
– Occult nipple-areolar complex
involvement reported in 8-50% of cases
• In the setting of prophylactic
mastectomy:
– Leaving more ductal epithelium behind
Prophylactic Nipple-Sparing
Mastectomy
• Prophylactic NAC-sparing mastectomy (NSM) in
BRCA1/2 mutation carriers is controversial over
concern regarding residual fibroglandular tissue
with malignant potential.
• University of Toronto
• Study modeled volume of fibroglandular tissue
in the NAC at a standard retroareolar margin
(5 mm) and examined the change in amount
with a greater retroareolar margin.
Baltzer HL, et al. Ann Surg Oncol 2014
Prophylactic Nipple-Sparing
Mastectomy
Baltzer HL, et al. Ann Surg Oncol 2014
MRI to assess fibroglandular tissue remaining after
nipple-sparing mastectomy
• 105 BRCA1/2 mutation carriers studied.
• At 5 mm retroareolar thickness, residual NAC
fibroglandular tissue (FGT) comprised 1.3%
of the total breast FGT.
• Increasing the retroareolar thickness to
10 mm led to a statistically significant
increase in the amount of NAC FGT
(p < 0.001, d = 1.1).
Baltzer HL, et al. Ann Surg Oncol 2014
Occult Malignancy within the NAC
Study # cases Occult Cancer
(%)
F/U
(mos)
Stolier 2008
Ann Surg Oncol
9
(BRCA)
0 N/A
de Alcantara Filho
Ann Surg Oncol 2011
79
(22 BRCA)
11 (5.6%)
(none at NAC)
10.4
(no LR)
Spear 2011
Plast Reconstr Surg
80 0
(1 LCIS)
42
(no LR)
Warren Peled 2012
Ann Surg Oncol
428
(37% RR)
In situ 1.7%
Invasive 1.4%
24
2% LR
Prophylactic Nipple-Sparing
Mastectomy
Evidence on the
Oncologic Safety
Oncologic Safety
What is the Evidence?
Oncologic Safety of NSM
• Systematic review of total skin-sparing
mastectomy
– 2000-2011, Medline and Cochrane databases
– 27 studies included, 3331 mastectomies
– 10 studies with oncologic outcomes, with
documented mean/median FU of 2 years
– Local-regional recurrence rate of 2.8%
• Concluded data support use of total skin-
sparing techniques
Piper M, et al. Ann Plast Surg, 2013
Oncologic Safety of NSM
• Systematic review with pooled analysis
– 1970-2013, PubMed and Ovid databases
• 48 studies selected, 6615 nipple-sparing
procedures
• Locoregional recurrence rate of 1.8%
• Distant metastasis rate 2.2%
• Concluded nipple-sparing mastectomy
appears to be oncologically safe in
appropriately selected patietns
Endara M, et al. Plast Reconstr Surg, 2013
NSM in BRCA Mutation Carriers
• 53 BRCA-mutation carriers undergoing TSSM
• 2001-2011, 26 prophylactic, 27 therapeutic
• Cases were age matched or stage matched
• Prophylactic TSSM – 1 case of in situ
carcinoma in the nipple (1.9%) vs. 3.8% in non-
BRCA cohort
• Mean follow-up of 51 months, no new cancers
in either cohort.
Peled AW, et al. Ann Surg Oncol, 2014
Nipple-Sparing Mastectomy
Importance of
Pathology
Pathologic Assessment
• Clips mark the circumference of the breast
tissue immediately underlying the areolar
margin (at 12, 3, 6, and 9 o’clock) with a fifth
clip on the breast tissue immediately
underlying the nipple
• Orient the breast specimen denoting the
SUPERIOR and LATERAL margins
• Specimen sent for immediate processing
• Specimen x-ray for extensive
microcalcifications
Nipple-Sparing Mastectomy
• Appropriately selected patients
• Ptosis
• Non-smokers
• Patients must be counseled regarding possible loss of:
• NAC
• Nipple sensation
• Nipple erectile function
Contralateral Prophylactic
Mastectomy in Patients
without Pathogenic Mutations
Trends in CPM
Yao K, et al. Ann Surg Oncol, 2010
CPM Rates by Primary Tumor Stage CPM Rates by Age
Rate of CPM – MD Anderson
• 2000-2006
• 2,504 patients with stage 0 to III unilateral primary breast cancer
• 1,223 (49%) underwent mastectomy
• 284 (23.2%) of those undergoing mastectomy underwent CPM
Yi M, et al. Cancer Prev Res, 2010
Rate of CPM – Outside USA
Guth U, et al. Eur J Surg Oncol, 2012
Risk of Contralateral Breast Cancer
• Overall risk varies, < 1% per year
• Higher in patients with BRCA mutation or strong family history
• Systemic treatments lower risk
• Risk constant over time
• vs systemic recurrence risk which is greatest 1-2 years after completion of therapy
Incidence of Contralateral Breast
Cancer (CBC) Declining
• 1975-2006 SEER
• ≈ 3% decrease/year of CBC since 1985
• Incidence of CBC among patients who presented with initial ER negative breast cancers have remained stable over time
• ↓ CBC rates likely due to widespread use of adjuvant endocrine therapy
Nichols H, et al. J Clin Oncol, 2011
Risk of CBC
• 1975-2006
• N=8053
• 7% developed CBC
• Median interval time between first and CBC = 4.6 years (range 6 mo – 27 yr)
• Rates have decreased over time
Vichapat V, et al. Eur J Cancer, 2011
Risk of Contralateral Breast Cancer
Development is Age Dependent
Vichapat et al, Eur J Cancer 2011
London, Cohort = 8,478 pts primary breast cancer
CPM: Factors to Consider
• Cumulative lifetime risk of CBC
• Age at diagnosis
• FH/BRCA mutation carrier
• Risk of death from index cancer
• Stage of index cancer
• Availability of non-surgical prevention options
• ER status
Survival Benefit of CPM?
• Cochrane review (Lostumbo et al, 2010)– 9 studies looking at CBC rate, 3 at DFS
– Consistent reports of decrease in CBC, inconsistent DFS results
• SEER database (Bedrosian et al, JNCI, 2010)– Improved 5yr DSS in ER- women with Stage I/II ER- BC (88.5% vs
83.7%, 4.8% difference)
– ER- pts had higher risk of CBC (0.46% vs 0.9%)
• Mayo series (Boughey et al, Ann Surg Oncol, 2010)
– 17 yr follow-up, CBC risk 0.5 vs 8.1% (95% decline)
– OS 83% in CPM pts with 74% in unilateral TM
• All retrospective studies; likely some selection bias as
survival differences greater than CBC rate…
Survival Benefit of CPM?
• Cochrane review (Carbine et al, 2018)
• 61 observational studies with some methodological limitations;
randomized trials were absent.
• 15,077 women with a wide range of risk factors for breast
cancer, who underwent RRM.
• Twenty-one BRRM studies looking at the incidence of breast
cancer or disease-specific mortality, or both, reported
reductions after BRRM, particularly for BRCA1/2mutations.
• Twenty-six CRRM studies consistently reported reductions in
incidence of contralateral breast cancer but were inconsistent
about improvements in disease-specific survival.
Survival Benefit of CPM?
• Cochrane review (Carbine et al, 2018)
• 7 studies attempted to control for multiple differences between
intervention groups and showed no overall survival advantage
for CRRM.
• Another study showed significantly improved survival following
CRRM, but after adjusting for BRRSO, the CRRM effect on all-
cause mortality was no longer significant.
• In women who have had cancer in one breast, CPM may
reduce the incidence of cancer in that other breast, but there is
insufficient evidence that this improves survival because of the
continuing risk of recurrence or metastases from the original
cancer. Thought should be given to other options to reduce
breast cancer risk, such as BRRSO and chemoprevention,
when considering RRM.
No. of Patients, (%)
Complication, typeReoperation, bleedingReoperation, otherInfectionFlap lossMastectomy skin flap necrosisCombinationNone
Complications, locationIndex breastContralateral breastBothNeither
9 (3.8)7 (2.9)7 (2.9)1 (0.4)8 (3.4)7 (2.9)
200 (83.7)
20 (8.4)15 (6.3)4 (1.7)
200 (83.7)
Goldflam et al, Cancer 2004
Balancing Risk and Benefit:Surgical Complications after CPM
239 pts with unilateral Stage 0, I or II
disease, CPM at MDACC between 1987-
1997; 92% with reconstruction
Would they choose CPM again?
J Clin Oncol 2005; 23(31):7849-7856
Impact of CPM on Patient
Satisfaction
MSKCC 294 patients immediate
implant reconstruction
– 182 No CPM
– 112 CPM
– Breast Q questionnaire administered
– Mean 52 months from surgery
Koslow et al Ann Surg Oncol, 2013
Patient Reported Satisfaction
CPM
Koslow et al Ann Surg Oncol, 2013
Summary
• PM is risk reducing, not risk eliminating
• Benefit is proportional to risk
• BRCA population WITHOUT cancer probably most likely to benefit
• Very little data about survival benefit - CPM
– Need to consider the odds of dying of index carcinoma compared to developing and dying of contralateral disease
• Young age plus early stage disease best candidates
• Reconstructive issues need to be considered
An Individualized Approach with
Shared Decision-Making
•Future Breast
Cancer Risk
•Cancer-related
Anxiety
•Surgical
Morbidity
•Body Image
•Psychosocial
concerns
Acknowledgements
Breast Surgical Oncology
Henry M. Kuerer, MD, PhD
Elizabeth A. Mittendorf, MD, PhD
Plastic & Reconstructive Surgery
David Adelman, MD
Donald Baumann, MD
Carrie Chu, MD
Mark Clemens, MD
Patrick Garvey, MD
Jesse Selber, MD