Journal of the National Cancer Center 1 (2021) 23–30

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Journal of the National Cancer Center

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Expert consensus on diagnosis, treatment and fertility management of

young breast cancer patients ✩
Committee of Diagnosis, Treatment, and Fertility Management of Chinese Young Breast Cancer Patients
Corresponding author: Fei Ma, Department of Medical Oncology, National Cancer Center/National Clinical
Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical
College, Beijing 100021, China. E-mail address: drmafei@126.com

a r t i c l e i n f o a b s t r a c t

Keywords: Breast cancer in young females is a relatively common disease in China. Young breast cancer has aggressive
Breast neoplasms clinical and pathological features. During the treatment of young females with breast cancer, issues involving
Young women the choice of surgical methods, early amenorrhea, and fertility protection may have physical, psychological, and
Diagnosis and treatment
social impacts. Thus, a multidisciplinary model of diagnosis and treatment is indispensable. The breast cancer
Fertility protection
expert committee of the National Cancer Quality Control Center organized experts in related fields in China to
Consensus
compile this consensus as to provide scientific and feasible solutions for rational diagnosis, treatment, and fertility
management for young females with breast cancer. This consensus is based on the literature data, the views of
relevant international guidelines, and the clinical practice experience of experts in different fields.

Characteristics of young Chinese breast cancer patients
Clinicopathological characteristics
Breast cancer is the most common cancer in Chinese females. In
China, the average age of breast cancer at diagnosis is 48.7 years, which
is nearly 10 years earlier than that of the European Union and the United
States.1 , 2 The definition of young breast cancer has always been contro-
versial. This consensus defines the age of onset ≤ 35 years as young
breast cancer. In developed countries, breast cancer patients younger
than 40 years old account for less than 7% of all breast cancer patients.
In China, young breast cancer patients account for more than 10% of
all breast cancer patients, and very young breast cancer patients (aged
≤ 25 years) account for about 0.5%.1 , 3
Young breast cancer is often associated with more advanced stages,
lower hormone receptor positivity, higher epidermal growth factor re-
ceptor 2 positivity, higher proportion of triple negative breast cancer
and lymph node metastasis, and worse prognosis.4–8 These clinicopatho-
logical features are even more prominent in very young breast cancer
patients.3 , 9
Genetic predisposition
Young breast cancer patients are more likely to carry pathogenic
or likely pathogenic germline mutations, making genetic screening for
young breast cancer necessary. Common genetic susceptibility for breast
cancer in Chinese population include mutations in BRCA1, BRCA2,
PALB2, TP53, ATM, RAD51D, RECQL, CHEK2, and BARD1.10 , 11 Young
breast cancer has a unique spectrum of mutation that confers genetic
susceptibility. The frequency of germline mutation in young breast can-
cer patients reaches 24.0%.9 Pathogenic mutations are usually associ-
ated with specific clinical phenotypes and prognosis, and are potential
targets for treatment. Patients with BRCA2 mutation are more likely
to develop luminal subtype, while triple-negative breast cancer is more
common in patients with BRCA1 mutation. Patients with germline mu-
tations display more aggressive clinical features, and studies have con-
firmed that patients with BRCA 1/2 mutation have worse overall sur-
vival and disease-free survival.10
The expert group’s opinions are as follows. First, young breast can-
cer patients should receive genetic counseling, regardless of whether
they have a cancer family history. In order to better develop a compre-
hensive treatment plan, genetic counseling should be carried out before
treatment. Patients should be informed that genetic testing may affect
their social relationship, psychology, screening strategy, and therapeu-
tic regimen. Second, young breast cancer should be tested for common
genetic susceptibility genes. In addition to BRCA1/2; PALB2, ATM, and
TP53 should also be tested. The standard procedure for interpretation
and clinical application of genetic testing is still under study and dis-

✩
Given his role as Editor, Fei Ma had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility
for the editorial process for this article was delegated to Huan He.

https://doi.org/10.1016/j.jncc.2021.02.001
Received 3 December 2020; Received in revised form 4 February 2021; Accepted 8 February 2021
2667-0054/© 2021 The Authors. Published by Elsevier B.V. on behalf of Chinese National Cancer Center. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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Committee of Diagnosis, Treatment, and Fertility Management of Chinese Young Breast Cancer Patients
cussion. It is recommended to refer to existing genetic and pathological
guidelines in China.12
Fertility management
The rapid progression in anti-tumor therapies has greatly improved
the long-term survival of breast cancer patients, but it also brings short-
term and long-term adverse effects including ovarian function damage.
The result of a population-based study showed that the pregnancy rate
of treated breast cancer patients is only 3%, which is 40% lower than
that of the general population.13 The fertility rate of breast cancer pa-
tients depends on the age of diagnosis and treatment plan. During treat-
ment, chemotherapy drugs such as cyclophosphamide can destroy ovar-
ian function, leading to early amenorrhea. Furthermore, endocrine ther-
apy for up to 5–10 years can cause young females to miss their optimal
reproductive age. Concerns about fertility issues may lead to patients’
reluctance to start or fail to adhere to anti-tumor therapy.14 Therefore,
the issue of fertility protection for patients with malignant tumors, es-
pecially young breast cancer patients, has attracted increasing attention
worldwide.
According to the guidelines for diagnosis and treatment of young
breast cancer patients formulated by the European Society of Medical
Oncology in 2017, young breast cancer patients should receive immedi-
ate consultation and advice from their physicians on fertility protection
at the time of diagnosis.15 In 2018, the American Society of Clinical
Oncology and the British Fertility Association successively updated the
guidelines of fertility protection for patients with malignant tumors, pro-
viding options of technical solutions from the perspective of assisted re-
productive technology.16 , 17 The fertility management guidelines in Eu-
ropean Union countries and the United States could be used as references
for clinical diagnosis and treatment of young breast cancer patients in
China.
Surgical treatment
Surgical treatment is an important part of the comprehensive treat-
ment of breast cancer. For young breast cancer patients, surgical treat-
ment needs to keep the balance between efficacy and complications.
Surgery for breast cancer involves the removal of breast tumor and
the staging of axillary lymph nodes. National Comprehensive Cancer
Network (NCCN) guidelines, the St. Gallen expert consensus, and the
Chinese Anti-Cancer Association guidelines recommended that breast-
conserving surgery is an option for female patients who meet the re-
lated criterias and have the desire to preserve breast. There is no signif-
icant difference in breast cancer-specific survival and overall survival
between breast-conserving surgery plus radiation and mastectomy in
young women aged < 40 years with early-stage breast cancer.18 , 19 The
result of a large population-based study showed that breast-conserving
surgery plus radiation had better breast cancer-specific survival and
overall survival than mastectomy, except in patients < 40 years with
T1–2N0–1 stage.20 For patients with clinically negative axillary lymph
nodes, sentinel lymph node biopsy can be selected for axillary lymph
node staging.21 Patients with BRCA germline mutation have a signifi-
cantly increased risk of contralateral breast cancer. It’s not clear whether
preventive contralateral mastectomy can prolong patient’s survival, be-
cause data based on the Chinese population is still lacking.
Breast-conserving treatment
The surgical treatment of young patients with operable breast can-
cer should follow surgical treatment guidelines. Studies have shown that
young patients have an increased risk of local recurrence after breast-
conserving surgery.22 , 23 At the 2016 American Society of Clinical On-
cology meeting, the results of a retrospective study in Denmark showed
that the local recurrence rate of breast-conserving surgery plus radio-
therapy is 13% higher than mastectomy without radiotherapy in early
24
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Journal of the National Cancer Center 1 (2021) 23–30
stage breast cancer females younger than 45 years without lymph node
metastasis. In a retrospective study of 2784 patients undergoing breast-
conserving surgery, the local recurrence rate of patients <35 years was
2.5%, which was higher than that of the overall population (1.1%).22
However, in a randomized controlled study with a follow-up of up to
20 years, there was no difference in overall survival and time to distant
metastasis between the breast-conserving surgery group and the mastec-
tomy group in stage I to II patients under 50 years.23 After discussion
and voting, our expert group recommended breast-conserving therapy
for young breast cancer patients who meet the indications. In terms of
the high risk of local recurrence, long-term follow-up is required. Young
females usually have dense breast glands, and nodules are likely to be
ignored. Breast enhancement MRI, ultrasound and/or X-ray examina-
tions should be performed before and after surgery to avoid multifocal,
multicentric lesions and residual cancer.
The association of molecular subtypes and the recurrence risk in
young breast cancer has not been verified in prospective studies. A meta-
analysis retrospectively analyzed the clinical data of 12,592 cases of
breast cancer with a median age of 51 years, including 7176 cases of
breast-conserving surgery and 5416 cases of mastectomy. The results
show that the local recurrence rate of patients with Luminal subtype is
lower than that of HER-2 overexpression and triple-negative breast can-
cer subtypes. The local recurrence rate of triple-negative breast cancer
patients is the highest in both surgical methods.24 Whether molecular
subtypes need to be considered when selecting surgical methods is still
controversial. However, it is recommended to strengthen follow-up for
patients with HER-2 overexpression and triple-negative breast cancer
after breast-conserving surgery.
BRCA1/2 germline mutation is a relative contraindication for breast
conserving surgery. The results of a long-term follow-up study in pa-
tients undergoing breast-conserving surgery showed that the recurrence
rate of ipsilateral breast cancer in mutation carriers at 10 and 15 years
was much higher than that in non-mutation carriers (12% vs 9%; 24%
vs 17%). The incidence of contralateral breast cancer in mutation car-
riers at 10 years and 15 years was 26% and 39%, compared to 3% and
7% in non-mutation carriers.25 For young breast cancer patients with
pathogenic mutations in BRCA1/2, physicians should explain the risks
of different surgical methods before surgery.
Breast-feeding problems after breast-conserving surgery
The ability of the affected breast to breastfeed after breast-
conserving surgery is a common concern of young female patients.
Surgery and radiotherapy may decrease the ductility of nipples, lead-
ing to breastfeeding difficulties on the affected side. In the case of are-
ola incisions and relatively high doses of radiotherapy, it is more likely
that the affected breast cannot secrete milk. In a retrospective study,
>50% of patients were able to produce milk from the affected breast,
although with decreased secretion volume, decreased fat content and
increased salt content. The lactation function of the contralateral breast
is not affected.26 Up to now, there is no high-level evidence-based clin-
ical research regarding the problems with breast-feeding after breast-
conserving surgery. Moreover, it may increase the risk of mastitis in the
affected breast during the period of breast-feeding. It is recommended
that patients choose breastfeeding or other alternative methods under
the premise of full notification.
Sentinel lymph node biopsy
Axillary lymph node staging offers important references for decision-
making about breast cancer treatment. Sentinel lymph node biopsy is
the first-choice recommendation for axillary staging in patients with
clinically negative axillary lymph node and non-inflammatory breast
cancer. The NSABP B32 study compared the overall survival, disease-
free survival, local recurrence risk and surgical complications of clini-
cally axillary-negative breast cancer patients undergoing sentinel lymph
Committee of Diagnosis, Treatment, and Fertility Management of Chinese Young Breast Cancer Patients
node biopsy or direct axillary dissection. There is no significant differ-
ence in the 8-year disease-free survival rate and local recurrence rate
across the two groups.27 Patients aged ≤49 years accounted for 26%
of the total population in the NSABP B32 study, but there is no ran-
domized controlled clinical study about the prognostic value of sentinel
lymph node biopsy specifically in young breast cancer patients. Com-
bined with the results of previous clinical research and current clinical
practices, it is recommended that young patients with clinically negative
axillary lymph nodes should prefer sentinel lymph node biopsy.
Oncoplastic surgery and breast reconstruction
Young breast cancer patients pay more attention to the appearance
of their breasts after surgery. Oncoplastic surgery is a good option
for young females who are candidates for breast-conserving surgery
or lumpectomy, which often leaves the breast distorted. Oncoplastic
surgery can partially restore the breast’s natural appearance and shape,
while helping to ensure a negative margin. Compared with breast-
conserving surgery, breast-conserving plus oncoplastic surgery had a
lower proportion of positive or close margins in a study of 1177 breast
cancer patients (5.8% vs 8.3%, P = 0.04).27 Compared with breast-
conserving surgery only, breast-conserving plus oncoplastic surgery has
a lower rate of re-excision and conversion to mastectomy.28 For those
with large tumors, the combination of oncoplastic surgery and neoadju-
vant therapy increases the chances of breast preservation and improves
the shape of the breast. Young breast cancer patients receiving breast-
conserving surgery are recommended to choose oncoplastic surgery to
improve the shape of the breast.
Many young breast cancer patients who do not meet the indications
for breast-conserving surgery have to receive mastectomy. Breast recon-
struction is a surgical method that rebuilds the shape and appearance
of the breast after mastectomy. Breast reconstruction can choose pri-
mary reconstruction or secondary reconstruction according to the pa-
tient’s body type and subsequent treatment plan. Breast reconstruction
surgery can be divided into immediate reconstruction and delayed re-
construction according to whether it is performed at the same time as
the mastectomy. Breast reconstruction can choose prosthesis reconstruc-
tion or autologous tissue reconstruction. If the nipple and areola are not
involved, mastectomy with preservation of the nipple and areola and
combined with reconstruction can be considered. The result of a retro-
spective study showed that there were no significant differences in local
recurrence, disease-free survival and overall survival between nipple-
preserving mastectomy and mastectomy in females aged <35 years.29
Breast reconstruction for young breast cancer patients can be planned
according to the age at diagnosis, the type of breast structure (compact
or fat), tumor staging, and adjuvant therapy. Patients with advanced
stages and poor prognosis need to be carefully evaluated for breast re-
construction.
Prophylactic mastectomy
For breast cancer patients with BRCA1 or BRCA2 germline mutation,
the annual incidence of contralateral breast cancer is 3%,30 much higher
than the 0.6% in the overall breast cancer population.31 Strategies to
reduce the risk of contralateral breast cancer include regular screening
through medical imaging, contralateral breast prophylactic mastectomy,
prophylactic salpingo-oophorectomy, and drug prevention. The most ef-
fective method is prophylactic mastectomy, which can reduce the risk by
95%.32 , 33 The proportion of young breast cancer patients in the United
States receiving prophylactic mastectomy has been increasing year by
year.34 Young breast cancer patients with BRCA1/2 mutation should be
fully informed of the high risk of developing contralateral breast cancer
and the advantages and disadvantages of preventive measures. Surgeons
must evaluate the patient’s family history, BRCA gene mutation status,
and obtain the patient’s informed consent before performing contralat-
eral prophylactic mastectomy.
25
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marzo 07, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
Journal of the National Cancer Center 1 (2021) 23–30
For young breast cancer patients without BRCA1/2 gene mutations,
there is no evidence that contralateral prophylactic mastectomy can re-
duce the risk of disease and improve survival. Therefore, other strate-
gies, such as postoperative endocrine therapy and regular imaging ex-
aminations, are recommended for reducing the risk of future disease.
Chemotherapy
Drug selection and precautions
Advances in the combination chemotherapy have decreased the risk
of recurrence and metastasis for breast cancer patients, especially ben-
efiting patients aged <50 years.31 Young breast cancer should actively
receive chemotherapy, but the age at diagnosis alone should not be the
main reason in terms of deciding on chemotherapy. Other factors should
also be taken into consideration when choosing chemotherapy regimen,
such as tumor staging and molecular subtype. If there are no other risk
factors, early young breast cancer with Luminal A subtype can receive
endocrine therapy only. For patients with middle- and high-risk recur-
rence; chemotherapy, targeted therapy, and endocrine therapy should
be performed based on the specific tumor staging and molecular sub-
type, with reference to the latest breast cancer diagnosis and treatment
guidelines.21
Young breast cancer patients with fertility needs should be fully in-
formed of the adverse effects of chemotherapy drugs on ovarian func-
tion. In particular, cyclophosphamide can cause fertility disorders and
increase the risk of infertility. The choice of adjuvant chemotherapy
drugs should follow existing guidelines, and patients should be fully
informed of the impact of cyclophosphamide on ovarian function and
the increased risk of infertility, as well as the significant increase in the
risk of early-onset ovarian insufficiency. It is recommended that young
breast cancer patients should receive gonadotropin releasing hormone
agonist (GnRHa) injection to protect ovarian function, starting 2 weeks
before adjuvant chemotherapy and lasting until the end of chemother-
apy.35 , 36
Fertility protection during chemotherapy
Young breast cancer patients with fertility requirements should re-
ceive fertility protection consultation from obstetrics and reproductive
specialists as soon as possible. Egg, embryo, and ovarian tissue freezing
are recommended for young females with strong fertility needs (see the
fertility management section). Receiving GnRHa during chemotherapy
can also protect ovarian function. Formulating a specific fertility protec-
tion strategy requires consideration of actual condition and economic
situation of each patient.
The best time to get pregnant for young breast cancer patients needs
to be determined according to their physical condition, pathological fea-
tures of breast cancer, therapeutic regimen, and risk of tumor recur-
rence.37
Endocrine therapy
Necessity and drug selection
In the 2017 Consensus of International guidelines for Young Breast
Cancer Patients, the European Medical Oncology Association proposed
tamoxifen as the standard treatment for young, premenopausal, and
hormone receptor-positive breast cancer patients with low risk of re-
currence.15 However, recent studies have shown that combination of
ovarian function suppression also benefits a portion of intermediate
and high-risk premenopausal patients.38 , 39 Selective estrogen receptor
modulators are recommended for low-risk patients; while treatment for
intermediate-risk patients should use ovarian suppression in combina-
tion with selective ER modulators or aromatase inhibitors. For patients
with high-risk features – suggested by involvement of ≥4 lymph nodes,
Committee of Diagnosis, Treatment, and Fertility Management of Chinese Young Breast Cancer Patients
≤35 years of age, histological grade 3, or polygenic tests – ovarian func-
tion suppression combined with aromatase inhibitors provides maximal
benefit.40
Treatment options
The 2011 EBCTCG meta-analysis further confirmed the long-term
benefits of 5-year tamoxifen therapy for hormone receptor positive pa-
tients.41 Further extending the therapeutic duration to 10 year reduces
occurrence of distant recurrence events, but whether long-term tamox-
ifen use increases the risk of endometrial cancer has not been reported
for young premenopausal breast cancer patients. Prolongation of en-
docrine therapy will delay childbirth, and may even force patients to
miss optimal age for childbearing.42 , 43 Caution must be taken with se-
lection of appropriate therapeutic regimens and durations.
The endometrial thickness of patients on long-term tamoxifen should
be closely monitored at a regular interval of 3 to 6 months. Although
endometrial thickness in premenopausal patients does not infer the ne-
cessity of a live biopsy, a thickened endometrium (>12 mm) suggests
need for special treatment such as progesterone therapy.
Ovarian function suppression
There are three methods of ovarian suppression available: surgi-
cal castration, radiotherapy castration, and medical castration. Surgi-
cal castration confers quick and effective lowering of estrogen to post-
menopausal levels, but it is a highly invasive and irreversible process
leading to permanent loss of fertility in young women.44 Clinical appli-
cation of radiotherapy castration is limited by frequent occurrence of
incomplete castration and adverse pelvic reaction despite ease of imple-
mentation and low cost.44 Medical castration, the least invasive method
with few adverse events and good reversibility, is the current first-line
choice for endocrine treatment of premenopausal breast cancer patients.
The SOFT study showed that most breast cancer patients received
ovarian function inhibitor after confirming their premenopausal status
within 8 months after the last chemotherapy. However, the median time
of ovarian function recovery is as long as 6 to 8 months after chemother-
apy, forcing delay of ovarian function suppression.45 Therefore, it is
recommended that GnRHa should be used sequentially after chemother-
apy. It has been shown that concurrent application of GnRHa along with
chemotherapy does not have negative impact on survival benefit.45–47
The optimal duration of GnRHa treatment remains controversial.
Previous clinical studies confirmed safety and tolerability of 2–3 years
treatment with GnRHa, but the TEXT and SOFT study both chose a 5-
year treatment course.48–51 Therefore, the recommended duration of
GnRHa adjuvant endocrine therapy is 2 to 5 years. In light of the
SOFT&TEXT study, GnRHa should be given for 5 years if in combina-
tion with an aromatase inhibitor. However, prolonged endocrine ther-
apy delays childbirth, and determination of optimal GnRHa therapy du-
ration needs comprehensive evaluation for each individual patient. The
monthly dosage and 3-month dosage forms of GnRHa show comparable
pathophysiological and clinical outcomes, and the 3-month dosage form
is also a reasonable choice.52
Adverse events
Previous studies have shown that tamoxifen is accompanied by nu-
merous adverse events, especially gynecological symptoms (hot flashes,
increased vaginal discharge and endometrial thickening) and cardio-
vascular events (thrombosis). Aromatase inhibitor often increases the
incidence of fracture and arthralgia. Tamoxifen combined with ovar-
ian function suppression may cause thrombosis, hot flashes and night
sweats. Aromatase inhibitor combined with ovarian suppression fre-
quently causes osteoporosis, fractures, and vaginal dryness. Despite dif-
ferent sets of adverse events, the choice between tamoxifen and aro-
matase inhibitors has no significant impact on the quality of life.53 , 54
However, early discontinuation of therapy is more common in the group
of exemestane combined with ovarian function suppression.46 , 55
26
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Journal of the National Cancer Center 1 (2021) 23–30
The evaluation of adverse events and toxicities are based on the sub-
jective patient-reported data. Therefore, physicians should fully com-
municate with patients and inform them of possible adverse events. Ap-
propriate endocrine therapy may help increase patients’ compliance and
improve their quality of life. Table 1 shows the adverse events and in-
tervention methods during treatment with GnRHa.
Fertility management
Providence of fertility management
Oncologists should actively discuss fertility preservation options
with patients in childbearing age and their spouses as soon as possi-
ble and make necessary referral to gynecologists or reproductive physi-
cians. The potential impacts of anti-tumor therapy on fertility should
be well-discussed before tumor treatment, making it possible to choose
a suitable fertility protection program and to minimize psychological
problems, such as depression caused by fertility decline or loss.
Physicians should highlight the fertility-related context of each treat-
ment stage, especially for young women with fertility needs. Future
medical activities such as post-treatment follow-ups and conception at-
tempts should take fertility-related aspects of previous anti-tumor thera-
pies into consideration. When necessary, the patients should be referred
to a gynecologist or reproductive specialist immediately. All related dis-
cussions should be recorded in the medical records.16 , 17
Multi-disciplinary model provides optimal consultation for manage-
ment of fertility declination for young women with breast cancer: of-
fering fertility preservation, providence of psychological support, and
comprehensive understanding of the risks of different technologies.16 , 17
Studies have shown that post-treatment pregnancy does not increase the
risk of early recurrence, and previous anti-tumor therapy does not sig-
nificantly increase the possibility of congenital fetal abnormalities or
genetic diseases in future pregnancies.16 , 17 , 56
Adjuvant endocrine therapy can delay the time to pregnancy and
even cause young women to miss the best time for childbirth, but it
is not recommended for patients to interrupt standard endocrine ther-
apy for fertility needs. For patients who have to interrupt endocrine
therapy due to childbirth, they must complete the remaining endocrine
therapy after completion of childbirth. Oncologists should clearly con-
vey the risk of tumor recurrence associated with therapy interruption
before the patients decide to discontinue endocrine therapy for child-
birth.16 , 17 Natural pregnancy is the first-line choice, but utilization of
assisted reproductive technology is acceptable with consideration of the
patient’s tolerance of invasive procedures.16 , 17
Contraception and pregnancy planning
Recommended contraception methods include physical barriers and
intrauterine devices without progesterone, while hormone contracep-
tives are strictly prohibited. Pregnancy planning requires comprehen-
sive consideration of physical condition, health status, tumor pathology,
and the risk of recurrence.57 Young breast cancer patients are recom-
mended to wait out the peak recurrence period of 2 to 3 years after the
end of adjuvant chemotherapy. However, high-risk patients and patients
requiring long-term adjuvant endocrine therapy should extend the ob-
servatory period to 5 years and longer. Although anti-cancer therapy
has not been reported to significantly increase the chance of congenital
fetal abnormalities or genetic diseases, a 6-month interval after the end
of anti-tumor treatment is generally recommended to avoid potential
risk on fetus health. In the situation of unintended pregnancy, gyne-
cology and oncologists should comprehensively evaluate the following
factors: the use of anti-tumor drugs in the first 3 months of pregnancy,
the impact of pregnancy on tumor treatment, and the possible impact
of antitumor drugs on fetal development. The patients and their fami-
lies should give informed consent on continuation or discontinuation of
pregnancy. Choosing to continue the pregnancy requires close monitor-
ing of both fetal development and tumor progression. Patients who have
Committee of Diagnosis, Treatment, and Fertility Management of Chinese Young Breast Cancer Patients Journal of the National Cancer Center 1 (2021) 23–30

Table 1
Recommendations for safety management of GnRHa.

Adverse events Drug intervention Non-drug intervention

Vasomotor symptoms
Hot flashes SSRI: paroxetine∗ acupuncture
Night sweats • SSRI and NRI (venlafaxine, suitable clothing
gabapentin, clonidine)
• traditional Chinese medicine such as
Kuntai capsule and botanical extract
of black cohosh, and treatment based
on syndrome differentiation

Vaginal symptoms
Vaginal dryness hormone-free lubricants vaginal moisturizer
Vaginal atrophy short-term topical use of –
proestradiene under the guidance of a
gynecologist
Sexual dysfunction
Loss of libido • hormone-free lubricants effective communication between
• topical use of proestradiene under doctors and patients, and relax
the guidance of a gynecologist

Skeletal muscle symptoms

Osteoporosis and fracture bisphosphonates, vitamin D and weight-bearing exercises, quit
calcium tablets smoking and limit alcohol,
Joint pain nonsteroidal anti-inflammatory drugs, lose weight, systemic resistance
especially COX-2 inhibitors and exercise, and physical therapy
vitamin D
∗
Concomitant paroxetine and tamoxifen is not recommended.
Abbreviation: SSRI, Selective serotonin reuptake inhibitor; NRI, Noradrenaline reuptake inhibitor; COX-2, cycloxygenase 2.

not completed their endocrine therapies are strongly recommended to
complete the remaining therapy after child delivery.
Fertility protection
Fertility protection methods for young breast cancer patients include
ovarian function suppression and assisted reproductive technologies.
Currently employed methods include oocyte freezing, embryo freezing,
ovarian tissue cryopreservation and transplantation, immature oocytes
in vitro maturation and preservation, and GnRHa drugs.
After in vitro fertilization using the patient’ eggs and her partner’s
sperm, embryo freezing is the most common and the most successful
way of fertility preservation. Embryo freezing, a mature technique with
30 years of practice, is suitable for married patients with stable mar-
tial relationships in which both partners agree on in vitro fertilization
and preservation of excess embryos. Cryopreserved embryos can be used
in future reproductive treatment. The live birth rate of frozen-thawed
embryo transfer is affected by the age of the patient at the time of
egg retrieval. The live birth rate of frozen embryos before chemother-
apy and/or radiotherapy is similar to that of the age-matched control
group.16 , 17 , 56
Oocyte freezing technology is suitable for patients who are unmar-
ried or to whom embryo freezing is unavailable, and require radiother-
apy, chemotherapy or ovariectomy that impair ovarian function. Vitrifi-
cation technology is a cost-effective method for oocyte freezing, which
improves the live birth rate of each recovered oocyte to about 6.4%,
with some variation due to the number of frozen oocytes and the age of
the patient at the time of freezing.16 , 17 , 55 According to the two doc-
uments, "Human Assisted Reproductive Technology Regulations" and
"Ethical Principles of Human Assisted Reproductive Technology and Hu-
man Sperm Banks”, promulgated by former Ministry of Health on June
27, 2003; it is legal for single women to request oocyte cryopreservation
for fertility preservation due to tumor treatment.58–60
In vitro maturation (IVM) of immature oocytes is a newly devel-
oped technique that has been commonly applied to treat polycystic
ovary syndrome, poor ovarian response, and restricted use of routine
ovulation inducer due its stimulatory effects on hormone-dependent tu-
mors. Due to technical complexity, IVM is carried out only in some as-
sisted reproductive centers, limiting its application to urgent patients
who cannot tolerate delay in anti-tumor therapy.16 , 17 , 61 IVM allows
retrieval of immature oocytes at any timepoint during the menstrual
cycle, which reduces the economic and time burden of hyperstimula-
tion programs and avoids ovarian hyperstimulation syndrome. How-
ever, the implantation rate of immature oocytes after in vitro cul-
ture is lower than that of mature oocytes. The combination of IVM
and ovarian tissue cryopreservation may be necessary to ensure higher
success rate. IVM has been applied in clinical practice in domestic
hospitals.
Cryopreservation and transplantation of ovarian tissue does not re-
quire ovarian stimulation or sexual maturity, so it is the only alterna-
tive method of fertility protection for children. Successful ovarian tissue
transplantation restores not only part of the fertility, but also the en-
docrine functions of the ovary.16 , 17 , 62 In addition, the cryopreservation
of ovarian tissue does not increase estrogen level, making it suitable
for young breast cancer patients. This rapidly developing technique has
gradually become routine clinical practice in developed countries such
as Germany and is getting more attention in clinical practice in China.
Moreover, the simultaneous application of ovarian tissue cryopreserva-
tion and IVM increases the possibility of applying this technology in
breast cancer patients.61 The long-term efficacy and safety of the above
fertility protection methods awaits further confirmation by clinical re-
search and long-term follow-up.16 , 17 , 63
Patients should be informed about the possibility of estrogen level in-
crease associated with ovarian stimulation necessary for oocyte and em-
bryo cryopreservation. They should understand the possibility of estro-
gen level increase promoting tumor cells proliferation. Numerous stud-
ies have shown that the application of aromatase inhibitors along with
ovarian stimulation schemes and subsequent pregnancy could reduce
the incidence of the above situations and the risk of tumor recurrence.16
Young breast cancer patients are highly recommended to choose a con-
trolled ovarian stimulation scheme, which reduces the increase in es-
trogen level.16 , 17 , 63–68 In this scheme, controlled ovarian stimulation
to egg retrieval takes about 2 weeks, and chemotherapy can be started
48 h after egg retrieval. Compared with the traditional gonadotropin
stimulation scheme, this menstruation-independent, controlled ovarian
stimulation scheme allows earlier start of chemotherapy. However, its
safety and efficacy await further validation.17

27

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marzo 07, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
Committee of Diagnosis, Treatment, and Fertility Management of Chinese Young Breast Cancer Patients
Fig. 1. Standardized procedure for the diagnosis, treatment and fertility management in young breast cancer patients.
∗
It is recommended to choose one or more methods of fertility protection.
For young breast cancer patients to whom standard fertility preser-
vation program cannot be implemented, short-term ovarian function
suppression with GnRHa can reduce chemotherapy-induced ovarian in-
sufficiency and offer partial protection to ovarian function. It is recom-
mended to administer GnRHa at a monthly basis, starting 2 weeks before
chemotherapy and lasting until 2 weeks after the end of chemotherapy.
However, the fertility preservation ability and efficacy of GnRHa re-
mains controversial, and GnRHa should not replace effective fertility
preservation methods.16 , 17
Standardized procedure for fertility management
Young breast cancer patients usually face unique physical, sociologi-
cal and psychological challenges. The diagnosis, treatment, and the fer-
tility management plan for young breast cancer should be formulated
by multidisciplinary collaboration incorporating oncology, radiology,
obstetrics, gynecologists, reproductive medicine, and psycho-oncology.
The ovarian function of young breast cancer patients should be assessed
immediately after pathological diagnosis of breast cancer. The need for
fertility preservation should be discussed before implementation of anti-
tumor therapies. Young breast cancer patients with need for fertility
preservation should consult relevant experts before starting any treat-
ment. Undersanding and informed consent on the mutual impacts of
tumor treatment and fertility is absolutely crucial. Physicians and pa-
tients need to work together based on individual situations, to choose
the most appropriate treatment option and fertility protection method
(Fig. 1).
Consensus directing members of the committee of diagnosis, treatment, and
fertility management of Chinese young breast cancer patients (In alphabeti-
cal order of last name). Alfred O. Mueck (Center of Endocrinology and
Menopause, University Women’s Hospital of Tübingen), Olivia Pagani
(Institute of Oncology of Southern Switzerland), Jie Qiao (Department of
Obstetrics and Gynecology, Peking University Third Hospital,), Yan Sun
(Department of Medical Oncology, National Cancer Center/National
Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy
of Medical Sciences and Peking Union Medical College), Binghe Xu (De-
partment of Medical Oncology, National Cancer Center/National Clin-
ical Research Center for Cancer/Cancer Hospital, Chinese Academy of
Medical Sciences and Peking Union Medical College)
Consensus professional members of the committee of diagnosis, treatment,
and fertility management of Chinese young breast cancer patients (In alpha-
betical order of last name). Li Cai (Department of Medical Oncology,
Harbin Medical University Cancer Hospital), Bo Chen (Department of
28
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Journal of the National Cancer Center 1 (2021) 23–30
Breast Surgery, the First Hospital of China Medical University), Qian-
jun Chen (Department of Breast, Guangdong Hospital of Traditional
Chinese Medicine), Rong Chen (Department of Obstetrics and Gyne-
cology, Peking Union Medical College Hospital, Chinese Academy of
Medical Sciences), Zhanhong Chen (Department of Breast Medical On-
cology, Zhejiang Cancer Hospital), Lin Cheng (Department of Breast
Surgery, Peking University People’s Hospital,), Jiuwei Cui (Cancer Cen-
ter, the First Hospital of Jilin University), Juan Du (Department of Gy-
necological Endocrinology, Beijing Obstetrics and Gynecology Hospital,
Capital Medical University), Zhaoqing Fan (Breast Center, Peking Uni-
versity Cancer Hospital and Institute), Yi Fang (Department of Breast
Surgery, National Cancer Center/National Clinical Research Center for
Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and
Peking Union Medical College), Hongyan Guo (Department of Obstet-
rics and Gynecology, Peking University Third Hospital), Guohui Han
(Department of Breast Surgery, Shanxi Cancer Hospital), Yuntao Xie
(Breast Center, Peking University Cancer Hospital and Institute), Jingjie
Li (Reproductive Medicine Research Centre, the Sixth Affiliated Hospi-
tal of Sun Yat-sen University), Junjie Li (Department of Breast Surgery
Fudan University Shanghai Cancer Center and Cancer Institute), Man
Li (Department of Medical Oncology, the Second Affiliated Hospital of
Dalian Medical University), Rong Li (Department of Obstetrics and Gy-
necology, Peking University Third Hospital), Xingrui Li (Department
of Breast and Thyroid Surgery, Tongji Hospital, Tongji Medical Col-
lege, Huazhong University of Science and Technology), Yanping Li (De-
partment of Breast Surgery, Beijing Shijitan Hospital), Xiaoyan Liang
(Reproductive Medicine Research Centre, the Sixth Affiliated Hospi-
tal of Sun Yat-sen University), Hong Liu (The Second Department of
Breast Cancer, Tianjin Medical University Cancer Institute and Hos-
pital), Guangyu Liu (Department of Breast Surgery, Fudan University
Shanghai Cancer Center and Cancer Institute), Haining Luo (Center for
Reproductive Medicine, Tianjin Central Hospital of Gynecology Obstet-
rics), Fei Ma (Department of Medical Oncology, National Cancer Cen-
ter/National Clinical Research Center for Cancer/Cancer Hospital, Chi-
nese Academy of Medical Sciences and Peking Union Medical College),
Li Ma (Breast Center, the Fourth Hospital of Hebei Medical Univer-
sity), Hongnan Mo (Department of Medical Oncology, National Can-
cer Center/National Clinical Research Center for Cancer/Cancer Hos-
pital, Chinese Academy of Medical Sciences and Peking Union Medical
College), Bo Pan (Department of Breast Surgery, Peking Union Medi-
cal College Hospital, Chinese Academy of Medical Sciences), Xiangyan
Ruan (Department of Gynecological Endocrinology, Beijing Obstetrics
and Gynecology Hospital, Capital Medical University), Jing Shang (De-
partment of Obstetrics and Gynecology, Peking University First Hos-
Committee of Diagnosis, Treatment, and Fertility Management of Chinese Young Breast Cancer Patients
pital), Huan Shen (Reproductive Medicine Center, Peking University
People’s Hospital), Yehui Shi (Department of Medical Oncology, Tian-
jin Medical University Cancer Institute and Hospital), Xiangyang Song
(Department of Breast and Thyroid Surgery, Zhejiang Provincial Peo-
ple’s Hospital), Gang Sun (Department of Breast and Head-neck On-
cology, the Affiliated Cancer Hospital of Xinjiang Medical University),
Tao Sun (Department of Medical Oncology, Cancer Hospital of China
Medical University, Liaoning Cancer Hospital and Institute), Zhong-
sheng Tong (Department of Breast Oncology, Tianjin Medical Univer-
sity Cancer Institute and Hospital), Donggui Wan (Department of On-
cology, China-Japan Friendship Hospital), Haibo Wang (Breast Health
Center, the Affiliated Hospital of Qingdao University), Hanbi Wang (De-
partment of Obstetrics and Gynecology, Peking Union Medical College
Hospital, Chinese Academy of Medical Sciences), Jiayu Wang (Depart-
ment of Medical Oncology, National Cancer Center/National Clinical
Research Center for Cancer/Cancer Hospital, Chinese Academy of Med-
ical Sciences and Peking Union Medical College), Jing Wang (Depart-
ment of Breast Surgery, National Cancer Center/National Clinical Re-
search Center for Cancer/Cancer Hospital, Chinese Academy of Medical
Sciences and Peking Union Medical College), Kun Wang (Department of
Breast Cancer, Cancer Center, Guangdong Provincial People’s Hospital),
Shusen Wang (Department of Medical Oncology, Cancer Center of Sun
Yat-sen University), Tao Wang (Fifth Medical Center, Chinese People’s
Liberation Army General Hospital), Dan Wu (Department of Medical
Oncology, Fifth Hospital of Xiamen), Ling Xu (Breast Disease Center,
Peking University First Hospital), Songqing Ye (Department of Surgi-
cal Oncology, Fujian Provincial Hospital), Peng Yuan (Department of
Medical Oncology, National Cancer Center/National Clinical Research
Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sci-
ences and Peking Union Medical College), Jian Zhang (Department of
Medical Oncology, Fudan University Shanghai Cancer Center), Qiang
Zhang (Department of Breast Surgery, Liaoning Cancer Hospital & Insti-
tute), Yongqiang Zhang (Department of Medical Oncology, Beijing Hos-
pital), Jie Zhao (Center for Reproductive Medicine, Peking University
Third Hospital), Weihong Zhao (Department of Medical Oncology, Chi-
nese People’s Liberation Army General Hospital), Li Zhu (Comprehen-
sive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University
School of Medicine), Yingjun Zhu (Department of Obstetrics and Gyne-
cology, Tianjin Central Hospital of Gynecology Obstetrics), Honglan Zhu
(Department of Gynecology, Peking University People’s Hospital).
Editorial assistant. Lixi Li (Department of Medical Oncology, National
Cancer Center/National Clinical Research Center for Cancer/Cancer
Hospital, Chinese Academy of Medical Sciences, Peking Union Medi-
cal College), Jiashu Han (MD program, Peking Union Medical College,
Chinese Academy of Medical Sciences).
Declaration of Competing Interest
The authors declare that they have no conflict of interests.
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