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