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How long does it take? How to use it? An article analyzes the application of ovarian function suppression in early breast cancer

 Last Update: 2022-09-15
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Author: Cause and effect

According to GLOBOCAN 2020 data^[1], breast cancer in women has surpassed lung cancer to become the most common cancer

Postoperative adjuvant endocrine therapy is the standard treatment regimen after surgery for patients with EBC, and with the release of a series of studies such as SOFT, TEXT, ASTRRA, HOBOE-2, selective estrogen receptor modulators (SERM), aromatase inhibitors (AI), and ovarian function suppression (OFS) have been shown to reduce the risk

First, the way and choice of OFS

Ofs way

The purpose of OFS is to reduce estrogen levels to postmenopausal levels as soon as possible, and the current methods of OFS are mainly surgery, radiation therapy, and drug treatment

(1) Bilateral ovarian surgical castration

Surgery consists of traditional surgical resection and laparoscopic surgical resection, which are invasive and irreversible

(2) Ovarian radiotherapy castration

Between 20% and 30% of patients cannot successfully achieve the effect of ovarian castration after radiotherapy, and the overall induced estrogen decline is significantly worse than that of oophorectomy, so clinical use is limited

(3) Drug castration

Gonadotropin-releasing hormone agonists (GnRH-a) are currently the most commonly used drugs for ovarian castration, under normal circumstances, the hypothalamic secretion of GnRH can stimulate the pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn stimulates ovarian secretion hormones, constituting a hypothalamic-pituitary-ovarian regulatory system
.

When exogenous GnRH-a occupies the GnRH receptor of the pituitary gland, the pituitary gland no longer responds to normal GnRH, resulting in the blockage of the hypothalamic-pituitary-ovarian axis, and the secretion of ovarian hormones is reduced to postmenopausal levels, which is similar
to that of surgical castration.

However, at the beginning of the first administration, it has a "flare up" effect (ignition effect), that is, the effect of temporary stimulation of FSH and LH elevation, resulting in a temporary increase in
ovarian hormone secretion.

Ofs of choice

An analysis of 11,538 patients in 15 studies ^[4] showed that offline drug-based OFS significantly improved patient-free survival (DFS) and overall survival (OS) compared with no OFS, while surgical castration or radiotherapy castration showed no significant improvement
in DFS and OS compared with no OFS.

Therefore, GnRHa is an ideal OFS method for premenopausal breast cancer patients
.

The 2016 ASCO Guideline Update on OFS also recommended drug castration (GnRHa) as the preferred of choice for OFS therapy ^[4].

GnRHa can rapidly reduce the serum estrogen level in women, reach the postmenopausal state, this effect is reversible after stopping the drug, and such drugs have been included in the scope of medical insurance, considering the invasiveness and irreversibility of surgery, as well as the limited effect of radiotherapy, so the 2021 "Expert Consensus on the Clinical Application of Ovarian Function Inhibition in Early Breast Cancer in China" recommends drug castration (GnRHa) as the first choice for premenopausal hormone receptor-positive early breast cancer OFS ^[5]
。

Second, which patients need OFS treatment

PART

About the adaptable population of OFS,

Different guides have different recommendations

In 2016

ASCO Guide

(1) Higher-risk patients should receive endocrine therapy containing OFS drugs;

(2) Low-risk patients do not need endocrine therapy containing OFS drugs;

(3) Patients who should receive adjuvant chemotherapy in stage II or III are recommended to receive endocrine therapy containing OFS drugs;

(4) High-risk patients who are considering the use of chemotherapy in stage I or II of the clinical stage may be considered endocrine therapy
containing OFS drugs.

In 2019

ESMO Guidelines for Early Breast Cancer ^[6].

For patients who require chemotherapy and recover menstrual periods after chemotherapy (especially in the first year, but acceptable in the first 2 years), the addition of OFS drugs
to endocrine therapy should be strongly considered.

In 2021

St.
Gallen Consensus^[7].

(1) High risk of recurrence is still in a premenopausal state after receiving chemotherapy;

(2) Clinical stage II breast cancer and the age ≤ 40 years;

(3) Clinical stage II breast cancer
.

In 2020

ESMO Guidelines ^[8].

(1) For patients with a higher risk of recurrence, GnRHa should be combined on the basis of SERM or AI;

(2) Young women with clinical stage I or II breast cancer who cannot take SERM (due to contraindications or serious adverse reactions) can receive GnRHa, oophorectomy or AI+GnRHa alone;

(3) Female patients with a high risk of recurrence, who use tamoxifen to restore ovarian function within 2 years after the end of chemotherapy, should consider combining GnRHa
.

PART

Ovarian function suppression for early breast cancer in China in 2021

Clinical application expert consensus recommendation ^[5].

SERM monotherapy is recommended for low-risk patients;
Patients with moderate to high-risk premenopausal hormone receptor-positive breast cancer are recommended to receive endocrine therapy with OFS;
Premenopausal patients treated with AI instead of SERM need to receive OFS treatment at the same time;
Patients with EBC who receive chemotherapy sequential SERM monotherapy are recommended to combine OFS therapy
on the basis of SERM if they are judged to be "non-menopausal patients" within 2 years.

PART

Premenopausal hormone receptor-positive early breast cancer

Clinical pathways for adjuvant endocrine ^{therapy [5}].

Premenopausal hormone receptor positive for early breast cancer
Low risk	Medium to high risk
SERM	Endocrine therapy in combination with OFS

PART

Risk factor stratification ^[5].

Degree of danger	Judging points
Degree of danger	Lymph node metastasis	ER/PR	Other situations
Low risk	feminine	masculine	At the same time, the following conditions are met: pT≤2cm; Histology Level I; LVI negative; HER2 negative; Age ≥ 35 years; Ki-67≤ 20% or median laboratory value; HER2 is negative and does not meet these conditions, but polygenic testing is low-risk
Medium-risk	Other cases that do not meet the low/high risk definition
Risk	1 to 3 positive	masculine	One of the following conditions: Histology LEVEL III; pT>5cm； HER2 positive; Polygenic testing is high risk
	1 to 3 positive	feminine	Any situation
	≥ 4 positives	Any situation	Any situation

3.
Definition of postmenopausal

The purpose of using OFS in patients with EBC is to enable patients to quickly reach a postmenopausal state, and the determination of menopausal status is crucial
for the choice of endocrine therapy.

Age and treatment-induced amenorrhea time, E2 levels, and FSH levels are indicators of menopausal status, which includes natural menopause and interventions
.

The use of AI in premenopausal patients may lead to: (1) AI-related premenopausal levels of estrogen can reduce the efficacy of AI, fail and may even increase the risk of breast cancer recurrence; (2) The ovulation-promoting effect of AI can cause unintended pregnancy
.

Therefore, patients with amenorrhea after chemotherapy or endocrine therapy need to repeatedly measure FSH and E2 levels to confirm that they are postmenopausal states before AI
can be applied.

Guidelines/Consensus

Definition of menopause

Guidelines and Norms for the Diagnosis and Treatment of Breast Cancer of the Chinese Anti-Cancer Association (2021)^[9].

(1) After bilateral oophorectomy;

(2) Patients aged ≥ 60 years;

(3) Patients < 60 years of age, natural menopause ≥ 12 months, FSH and E2 levels in the postmenopausal range without chemotherapy, tamoxifen, torremidefen or ovarian castration in the past 1 year;

(4) Patients aged < 60 years who are taking tamoxifen or torremifen, FSH and E2 levels are in the postmenopausal range<b10>.

"Criteria for Judging Menopause after Adjuvant Therapy for Breast Cancer Patients in Premenopausal Women in China and Consensus on the Clinical Application of Aromatase Inhibitors (Draft Amendment)" ^[10].

(1) Patients ≥ 50 years of age, amenorrhea for at least 12 months after chemotherapy or during the period of taking SERM drugs, and the E2 and FSH levels have been measured at least 3 times in a row to reach the postmenopausal level;

(2) Patients aged 45 to 50 years old who have amenorrhea for at least 24 months after chemotherapy or during the period of taking SERM drugs, and the E2 and FSH levels have been measured at least 3 times in a row to reach the postmenopausal level;

(3) Patients who are less than 45 years old, due to the high probability of ovarian function recovery, in principle, this standard
is not applicable.

There are some differences in the definition of menopause between the two guidelines/consensus, the former being based on foreign guidelines and the latter being developed in combination with the median age of actual menopause in Chinese women and the operability of clinical practice
.

Both guidelines and consensus state that patients after bilateral oophorectomy are postmenopausal; The menstrual status of patients undergoing LHRH antagonists/agonists cannot be judged; If the person has not been menopausal before chemotherapy, the amenorrhea caused by chemotherapy cannot be judged to be a postmenopausal state
.

Iv.
How to choose the OFS joint program:

Combined AI? Joint SERM?

In the SOFT study ^[11], on the basis of postoperative standard adjuvant therapy, of which OFS combined tamoxifen (TAM) was compared to TAM for 5 years, the results of the 8-year follow-up showed that the OFS combination regimen was able to significantly improve DFS in premenopausal patients, and the absolute benefit of DFS in ofs+AI regimen was increased by 7%, compared with single-agent TAM, OFS+AI's 8-year distant recurrence-free interval, DRFI) benefit increased by 2.
8%.

Subgroup analysis showed that patients benefiting from of-combination of OFS were more likely to be node-positive, histologically graded 2 to 3, and tumors with a tumor diameter greater than 2 cm
.

In patients with node-negative, G1, T<2 cm, subgroup analysis showed limited benefit from OFS plus endocrine therapy, so the basic choice strategy for postoperative adjuvant endocrine therapy in such patients was recommended to be TAM for 5 years
.

A 2018 combined text & SOFT analysis^[12] published in the New England Journal of Medicine compared the efficacy of postoperative adjuvant endocrine therapy based on the use of OFS in combination with TAM 5 years and AI 5 years: IT was found that OFS combined with AI significantly improved prognosis
in the overall population.

Compared with OFS and TAM, OFS and AI showed sustained DFS improvement, with 8-year DFS rates of 82.
8% and 86.
8%, respectively, and an absolute benefit rate of 4%.

The 8-year no-relapse rate was 89.
7% and 91.
8%, respectively, and the absolute benefit rate was 2.
1%.

Among HER2-negative patients (86%), OFS combined with AI improved prognosis in all subgroups; OFS combined with AI had a significant clinical benefit in HER2-negative and high-risk patients requiring chemotherapy, with absolute DFS yields of 6.
9% and 9.
2%, and DRFI absolute benefits of 5% and 7%,
respectively, in the TEXT and SOFT studies.

The benefits of OFS combined with AI therapy for 5 years were confirmed
.

Further comprehensive quantitative analysis methods show that the factors associated with the absolute benefit of OFS and AI are <35 years of age, ≥ 4 lymph nodes are positive, and histological grade 3, suggesting that patients with these factors are more likely to benefit from OFS combined AI therapy
.

Subpopulation treatment effect pattern plot (STEPP) analysis based on the SOFT&TEXT study ^[13]: Patients included in premenopausal HR+/HER2-, who assessed the absolute benefit of a 5-year breast cancer-free interval (BCFI) by a comprehensive recurrence risk score, showed that The absolute benefit rate of OFS combined with AI compared to TAM monotherapy in patients at high risk of recurrence was 10% to 15% of BCFI at high risk of recurrence.
The absolute benefit rate of 5-year BCFI in patients at risk of moderate-risk recurrence is at least 5%; The absolute benefit of a 5-year BCFI in very low-risk patients is limited
.

The results of the HOBOE-2 study, a Phase III parallel controlled study in which 1065 patients were randomly placed in three treatment groups, namely tamoxifen plus tripralin (TAM+OFS), letrozole combined with trepresentin (AI+OFS), and zoledronic acid plus letrozole and treprelin (zoledronic acid + AI+OFS)
were presented at ESMO 2018.

The median age of patients was 45 years and the median follow-up was 65 months
.

The results showed that the 5-year DFS rate of 5-year Zoledronic acid + AI+OFS vs.
5-year AI+OFS vs.
5-year TAM+OFS in premenopausal HR-positive early-stage breast cancer was 93.
3%, 93.
2% and 85.
4%, respectively, and the absolute DFS benefit rate of 5-year OFS+AI compared with 5-year OFS+TAM was 7.
8%; On this basis, the combination of zoledronic acid significantly improved DFS compared with 5 years of OFS+TAM, reducing the risk of disease development by 48%, and the absolute benefit rate was 7.
9%.

According to the results of the MonarchE study ^[14], a 2-year increase in abexiline on an endocrine basis in patients with selected high-risk (high-risk factors including ≥ 4 lymph nodes positive or 1-3 lymph nodes positive or T≥5 cm, G3, Ki67≥20%) can further reduce the risk of recurrence in patients, with a two-year survival without invasive disease (IDFS) rate of 92.
2% vs.
88.
7%,
respectively.

In premenopausal patients, standard endocrine therapy should be selected based on the patient's risk of recurrence, followed by a combination of 2 years of abexil therapy
.

Therefore, OFS plus AI therapy is currently recommended for patients with moderate- and high-risk premenopausal HR-positive early-stage breast cancer, or higher-risk patients analyzed by STEPP, and OFS plus SERM therapy is also a reasonable choice
.

For patients with any risk level of contraindications to SERM, OFS in combination with AI is recommended
.

The 2022 CSCO Guidelines recommend:

For patients who are positive for lymph nodes 1-3 and meet one of the G3, T≥5 cm, Ki67≥ 20% of patients choose OFS + TAM for 5 years + abecili for 2 years (1A) or ofS + TAM (2A);
Use OFS + SERM for 5 years in patients with 1-3 lymph nodes positive and no other risk factors or node negative and with G2 or G3, T>2 cm, one of the high Ki67;
Use of OFS + AI for 5 years in patients with 4 or more lymph node positives
.

V.
Timing of of ofus: Synchronized with chemotherapy? Wait for the end of chemotherapy and confirm the premenopausal status to be used sequentially?

There are currently several studies exploring the timing of of of-use of OFS
.

study	method	outcome
ASTRRA study ^[15].	Baseline assessment of ovarian function is performed within 3 months after the last chemotherapy and ovarian function assessment is performed every 6 months for 2 years, randomized when evaluating premenopausal patients, and patients induced by chemotherapy induction of amenorrhea are first given oral TAM to evaluate the efficacy of TAM (5 years) + OFS (2 years) versus TAM (5 years).	OFS+TAM Group vs. The 5-year DFS rates in the TAM monotherapy group were 91. 1% and 87. 5%, respectively.
TEXT study ^[11].	Patients planning to undergo chemotherapy receive a regimen of of OFS concurrent chemotherapy.	OfS+AI vs. OFS+TAM had 5-year DFS rates of 89. 8% and 84. 6%, respectively, and 8-year DFS rates of 86. 8% and 82. 8%, respectively.
SOFT research ^[11].	Patients enrolled in chemotherapy who receive chemotherapy receive OFS after the status of premenopausals is confirmed within 8 months of the last chemotherapy session.	OfS+AI vs. OFS+TAM had 5-year DFS rates of 84. 3% and 80. 6%, respectively, and 8-year DFS rates of 85. 9% and 83. 2%, respectively.
PROMISE study ^[16].	Premenopausal patients receive chemotherapy with GnRHa versus chemotherapy .	The five-year DFS rate between the two groups was 80. 5% and 83. 7%, respectively.

In the SOFT and ASTRRA studies, GnRHa was used after chemotherapy confirmed premenopausal status, which avoided the unnecessary use of GnRHa
in some patients with permanent ovarian damage due to chemotherapy.

In the ASTRRA study, the observation time is even as long as 2 years, 95.
1% of patients recover ovarian function after 2 years after the end of chemotherapy, and too long waiting will cause some patients to lose the opportunity to
receive OFS and AI treatment.

Therefore, the current domestic consensus recommends ^[5]: according to the ovarian function status of hormone receptor-positive breast cancer before chemotherapy, the adjuvant endocrine therapy regimen is
decided.

If ovarian protection is considered, simultaneous chemotherapy with GnRHa is recommended without affecting the patient's survival benefit; If ovarian protection is not considered, it is recommended that GnRHa be used directly after chemotherapy is completed
.

It is not recommended to use GnRHa
after confirming the functional status of the ovaries in patients who have received chemotherapy.

Sixth, the best course of treatment for OFS:

2 years? 3 years? 5 years? Or is it longer?

Regarding the optimal course of GnRHa in the treatment of premenopausal breast cancer, there is no conclusive conclusion
.

Previous important clinical studies on GnRHa for adjuvant therapy for premenopausal breast cancer have used a 2-, 3- or 5-year course of OFS, such as GnRHa in the ZIPP study of 2 years, GnRHa in the ABCSG-12 study of 3 years, and GnRHa in soft and TEXT studies of 5 years, all of which confirm the good safety and tolerability of
GnRHa.

The SOFT study showed that the 5-year DFS rate, breast cancer-free survival rate and OS rate of GnRHa combined with TAM were 86.
6%, 88.
4% and 96.
7%, respectively, and the 8-year DFS rate, breast cancer-free survival rate and OS rate were 83.
2%, 89.
4% and 93.
3%,
respectively.

The results of the HOBOE-2 study showed that the 5-year DFS rates of 5-year zoledronic acid combined with AI and OFS, 5-year AI combined OFS, and 5-year TAM combined OFS were 93.
3%, 93.
2%, and 85.
4%,
respectively.

Although the asTRRA study received only 2 years of treatment with OFS, the population included were patients with early-stage breast cancer who had received (new) adjuvant chemotherapy and had not been menopausal or used TAM to subsequently restore ovarian function, and the results confirmed that the 5-year combination of TAM5 years combined with OFS 2 years compared with TAM5 years significantly improved the 5-year DFS rate (91.
1% vs 87.
5%) and the 5-year OS rate (99.
4% vs 97.
8%)
.

The duration of treatment in the baseline E study, PALLAS study, and PENELOPE-B study selected for the baseline E study, PALLAS study, and PENELOPE-B study selected by CDK4/6 inhibitors in high-risk breast cancer patients with early hormone receptor-positive breast cancer was also at least 5 years
.

However, there is no comparative study of different treatment courses of GnRHa, and based on the concept of prolonged treatment of endocrine therapy and the long-term follow-up results of the SOFT/TEXT trial, the domestic consensus recommends that the standard course of adjuvant GnRHa be 5 years ^[5].

Prolonged AI therapy after 5 years of AI treatment has been shown to have clinical benefits, so is there a benefit to extending OFS treatment again for patients who have completed 5 years of OFS treatment?

The 2021 St.
Gallen International Breast Cancer Conference voted on this topic: for patients who have completed 5 years of OFS+SERM treatment, if they are still in a premenopausal state, 41% of expert group members recommend continuing OFS+AI, and 45% of expert group members recommend continuing TAM treatment for 5 years
.

The 2021 edition of the Chinese early breast cancer ovarian function suppression clinical application expert consensus recommends that the standard course of GnRHa adjuvant endocrine therapy should be 5 years
.

After completion of 5-year endocrine therapy with OFS, if it is not menopausal and well tolerated, it is recommended to continue 5-year endocrine therapy with OFS or 5-year SERM therapy
.

In low-risk patients who choose OFS instead of chemotherapy, OFS plus endocrine therapy may be considered for a period of 2 years
.

The 2022 CSCO guidelines recommend SERM (TAM) for 5 years or OFS+AI for 5 years (class 2B evidence)
for those who have not been menopausal after completing the initial 5-year treatment of OFS+AI and are well tolerated.

Therefore, based on evidence of the benefits of prolonged endocrine therapy, prolonged OFS+ endocrine therapy may be recommended for patients who can tolerate nonmenopausals
.

7.
How is OFS applied to the protection of ovarian function in premenopausal EBC patients?

Ovarian damage caused by chemotherapy is irreversible, the number of follicles in women has been fixed since birth and no longer increases, and the apoptosis of follicle cells caused by chemotherapy will directly deplete the reserve of the ovaries and induce ovarian fibrosis
.

Chemotherapy-induced ovarian function damage and cumulative dose
of chemotherapy regimens and chemotherapy drugs.

A meta-analysis of 873 patients in five studies showed that ^the rates of premature ovarian function in the GnRHa group and control group were 14.
1% and 30.
9%,
respectively.

Post-treatment pregnancy rates were 10.
3% and 5.
5%,
respectively.

There were no statistically significant differences in DFS and OS across the
population.

Subgroup analysis was performed according to estrogen receptor status with no significant interaction
.

The study confirms that GnRHa is a viable option that reduces the risk of chemotherapy-induced premature ovarian failure and improves future fertility in patients with early premenopausal breast cancer
.

Therefore, several current guidelines recommend OFS for ovarian functional protection during chemotherapy:

ESMO 4th Edition International Consensus Guidelines for Young Breast Cancer	During (neo)adjuvant chemotherapy, GnRHa should be used simultaneously to reduce the risk of premature ovarian failure, protect ovarian function and reduce damage to fertility. GnRHa is not a substitute for established fertility preservation methods and should be offered to all young patients .
Guidelines for ESMO early-stage breast cancer 2019	Ofs during chemotherapy has a protective effect on ovarian function and has no adverse effect on patient prognosis, so it should be recommended to patients. However, in cases of wanting to conceive, OFS should not be the only way to preserve fertility.
Guidelines and Specifications for the Diagnosis and Treatment of Breast Cancer of the Chinese Anti-Cancer Association (2021 Edition)	Premenopausal patients (including hormone receptor positive or negative) are recommended to consider ovarian function inhibition drugs to protect ovarian function during adjuvant chemotherapy, and 1 to 2 weeks before chemotherapy is recommended, and the last dose is given 2 weeks after chemotherapy . Patients with pregnancy needs are recommended to consult an assisted reproduction department.

Therefore, the current domestic consensus ^{recommends [5]}: for patients with premenopausal breast cancer, regardless of hormone receptor positivity or negative, it is recommended to use ovarian function inhibition drugs before (new) adjuvant chemotherapy and during chemotherapy to protect ovarian function, reduce the risk of premature ovarian function failure, and reduce fertility damage
.

It is recommended to start GnRHa 2 weeks before chemotherapy and use it every 28 days until the last dose is given 2 weeks after the end of chemotherapy
.

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Reviewer: Jiang Zhou

Typography: Jiang Zhou

Execution: Traveller

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