4

Commentary by

he genes BRCA1 and BRCA2 are the

most well-studied genes that correlate

with risk of breast cancer. This family has

another type of gene with mutations, CHEK2,

a tumor-suppressor gene involved in

pathways of DNA repair and cell cycle

regulation.

Although CHEK2 mutations are rare, in

carriers with no affected relative, the risk of

breast cancer is approximately 20%, and it

increases up to 44% when both first- and

second-degree relatives are affected.1

All women testing positive for CHEK2

mutation should be referred to a breast

surveillance program for appropriate

screening and discussion of a management

plan. This interaction allows the woman and

her gynecologist to discuss breast screening

and initiate appropriate referrals.

There is no literature regarding CHEK2

mutations and hormone therapy (HT) or oral

contraception pill (OCP) use. As such,

recommendations are extrapolated from

BRCA literature, particularly from the

unaffected, BRCA mutation-carrier

population.

An unaffected woman with a CHEK2

mutation who has menopause symptoms

should review her management options with

and without HT.

Results from the Women’s Health Initiative

suggest a nonsignificant reduced risk

of breast cancer for estrogen-only therapy

(ET) and an increased risk with

combination conjugated equine estrogens-

medroxyprogesterone acetate therapy

(EPT).2

Extrapolating data from studies of BRCA1

and BRCA2 mutations, there is a theoretical

increased risk of breast cancer in women with

CHEK2 mutations not undergoing risk-

reducing mastectomy, but although limited,

the data do not show an increased risk of

breast cancer in carriers of the BRCA

mutation who underwent risk-reducing

bilateral salpingo-oophorectomy (RRSO),

particularly with ET.3-6

The Two-Sister Study evaluated more than

1,400 sister-matched cases of breast cancer

and found no increased risk of breast cancer

with use of EPT, whereas unopposed

estrogen was associated with a reduced risk

of young-onset breast cancer.7 Thus, young

women undergoing RRSO do not appear to

be at increased risk for breast cancer should

they choose to start HT.

Ideally, any premenopausal woman will

undergo counseling regarding symptoms she

may experience, and options should be

individualized to her as a “plan” before

undergoing any risk-reducing surgery.

The choice of HT should be dictated by

symptoms—generalized versus localized—

and should be limited to the smallest dose for

the shortest period. In addition, those

undergoing concurrent mastectomy or who

T

Mercedes Castiel MD,

FRCSC, FACOG

Director of Women’s

Health Survivorship

University of Chicago

Medicine

Chicago, Illinois

5

already have undergone prophylactic

mastectomy are ideal candidates for HT.

Local vaginal estrogen is minimally absorbed

and can be used for the management of the

genitourinary syndrome of menopause in this

population or in women who are survivors of

breast cancer.8,9

Although somewhat limited, existing data

indicate that the risk of breast cancer is not

increased with use of systemic HT by

menopausal carriers of the BRCA mutation

with intact breasts.5 Extrapolating again from

unaffected carriers of the BRCA mutation,

HT can be used in carriers of the CHEK2

mutation.

It has long been acknowledged that oral

contraceptives (OCs) reduce the risk of

ovarian cancer in the general population10-13

as well as in the BRCA-mutation population.

For this reason, unaffected BRCA-mutation

carriers are often advised to use OCs

regardless of whether they are undergoing

RRSO.

This same benefit does not apply to carriers

of the CHEK2 mutation beyond the

decreased risk attributed to the general

population because there is no known

increased risk of gynecologic cancers

associated with CHEK2 mutations. However,

although there are some inconsistent data,

there does not appear to be an increased risk

of breast cancer in carriers of the BRCA

mutation using OCs.11,14

This 57-year-old woman is at risk for

contralateral breast cancer and is discussing

options with genetic counselors and her

breast surgeon. Unlike with BRCA mutations,

there is no known additional risk of

gynecologic cancers in carriers of the

CHEK2 mutation. Thus, no additional

intervention or evaluation is recommended to

prevent gynecologic cancers.

The patient’s sister can safely use HT, but

treatment should be individualized on the

basis of her symptoms. As with the general

population, it is recommended that symptoms

be monitored and reassessed periodically so

that treatment can be used for the shortest

time possible and at the lowest possible

dose.14

The patient’s 25-year-old daughter should be

counseled regarding contraception options as

one would counsel any young woman who

does not carry the CHEK2 mutation. The

OCs remain an option for her with little or no

risk of breast cancer.

For affected women who are positive for the

CHEK2 mutation, as for affected women who

are positive for the BRCA mutation,

nonhormone options should be explored

before initiating HT or OCs for quality-of-

life issues. The benefits of therapy need to be

weighed against the risks.

References

1. Cybulski C, Wokolorczyk D, Jakubowska A, et al.

Risk of breast cancer in women with a CHEK2

mutation with and without a family history of breast

cancer. J Clin Oncol. 2011;29(28):3747–3752. 2. Chlebowski RT, Anderson GL, Gass M, et al; WHI

Investigators. Estrogen plus progestin and breast

cancer incidence and mortality in postmenopausal

women. JAMA. 2010;304(15):1684-1692. 3. Birrer N, Chinchila C, Del Carmen M, Dizon DS. Is

hormone replacement therapy safe in women with a

BRCA mutation? A systematic review of the

contemporary literature. Am J Clin Oncol.

2018;41(3):313-315. 4. Mavaddat N, Peock S, Frost D, et al; EMBRACE.

Cancer risks for BRCA1 and BRCA2 mutation

carriers: results from the prospective analysis of

EMBRACE. J Natl Cancer Inst. 2013;105(11):

812-822.

6

Have you ever encountered a patient in whom an expanded gene panel

revealed a CHEK2 mutation? How did you proceed? Visit our

Member Forum to discuss the May Menopause e-Consult.

5. Domchek S, Kaunitz AM. Use of systemic hormone

therapy in BRCA mutation carriers. Menopause.

2016;23(9):1026-1027. 6. Domchek SM, Friebel T, Neuhausean SL, et al;

PROSE Consortium. Is hormone replacement therapy

(HRT) following risk-reducing salpingo-

oophorectomy (RRSO) in BRCA-1 (B1)- and BRCA-

2 (B2)-mutation carriers associated with an increased

risk of breast cancer [abstract]? J Clin Oncol.

2011;29(15 suppl):29S. Abstract 1501. 7. O’Brien KM, Fei C, Sandler DP, Nichols HB,

DeRoo LA, Weinberg CR. Hormone therapy and

young-onset breast cancer. Am J Epidemiol.

2015;181(10):799-807. 8. Goldfarb SB, Dickler M, Dnistrian A, et al. Limited

absorption of low dose 10 µg intravaginal 17-β

estradiol (Vagifem®) in postmenopausal women with

breast cancer on aromatase inhibitors [abstract].

Cancer Res. 2014;72(24 suppl). Abstract P2-12-05. 9. Goldfarb SB, Dickler MN, Dnistrian AM, et al. Use of

intravaginal 17-β estradiol to improve sexual function

and menopausal symptoms in postmenopausal women

with breast cancer on aromatase inhibitors [abstract].

J Clin Oncol. 2013:31(15 suppl). Abstract 9610.

10. Iodice S, Barile M, Rotmensz N, et al. Oral

contraceptive use and breast or ovarian cancer risk in

BRCA1/2 carriers: a meta-analysis. Eur J Cancer.

2010;46(12):2275-2284. 11. Marchbanks PA, McDonald JA, Wilson HG, et al.

Oral contraceptives and the risk of breast cancer.

N Engl J Med. 2002;346(26):2025-2032. 12. Vessey M, Yeates D. Oral contraceptive use and

cancer: final report from the Oxford-Family Planning

Association contraceptive study. Contraception.

2013;88(6):678-683. 13. McLaughlin JR, Risch HA, Lubinski J, et al;

Hereditary Ovarian Cancer Clinical Study Group.

Reproductive risk factors for ovarian cancer in carriers

of BRCA1 or BRCA 2 mutations: a case-control

study. Lancet Oncol.2007;8(1):26-34. 14. The NAMS Hormone Therapy Position Statement

Advisory Panel. The 2017 hormone therapy position

statement of The North American Menopause Society.

Menopause. 2017;24(7):728-753.

Disclosure: Dr. Castiel reports Consultant:

Cooper Surgical.

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