Commentary by · Commentary by he genes BRCA1 and BRCA2 are the most well-studied genes that...
Transcript of Commentary by · Commentary by he genes BRCA1 and BRCA2 are the most well-studied genes that...
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.
Menopause e-Consult® is a registered trademark
of The North American Menopause Society
Copyright © 2019 The North American Menopause Society
All rights reserved
30100 Chagrin Blvd, Suite 210
Pepper Pike, OH 44124, USA
Tel 440-442-7550 • Fax 440-442-2660 • [email protected]
www.menopause.org