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Paclitaxel

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Docetaxel

Albumin-Bound Paclitaxel

Leuprolide

Goserelin

Triptorelin Pamoate

Taxane

Antineoplastic Agents, Hormonal

Contraceptive Agents

Contraceptive Agents, Female

Contraceptive Agents, Hormonal

After randomization, patients in the experimental arm (Arm A) will receive GnRH agonist injection within 3 days of randomization and during neoadjuvant chemotherapy treatment. The protocol-defined chemotherapy will be given 7 to 14 days after GnRH agonist injection. The choice of GnRH agonist, including goserelin, leuprorelin and triptorelin giving in monthly, three-monthly or sixth-monthly, will be made by per investigator's discretion.

* Anthracycline/cyclophosphamide combination or dose-dense schedule: anthracycline/cyclophosphamide combination (Use of dose-dense schedule or not will be stratified.)
* Taxane (docetaxel or paclitaxel) ± optional platinum (Use of platinum or not will be stratified.)

* Anthracycline/cyclophosphamide combination or dose-dense schedule: anthracycline/cyclophosphamide combination (Use of dose-dense schedule or not will be stratified.)
* Taxane (docetaxel or paclitaxel) ± optional platinum (Use of platinum or not will be stratified.)

After randomization, patients in the experimental arm (Arm A) will receive GnRH agonist injection within 3 days of randomization and during neoadjuvant chemotherapy treatment. The choice of GnRH agonist, including goserelin, leuprorelin and triptorelin giving in monthly, three-monthly or sixth-monthly, will be made by per investigator's discretion.

Goserelin Acetate 3.6mg、Goserelin Acetate 10.8mg、Leuprolide Acetate 3.75mg、Leuprorelin Acetate 22.5mg、Triptorelin pamoate 11.25mg、Triptorelin pamoate 22.5mg

Chaio Lo, M.D.

Yen-Shen Lu, Ph.D.

Breast cancer (BC), especially premenopausal, is emerging rapidly in East Asia in recent 20 years. Half of the breast cancer patients in Asia are younger than 50 years of age. In general, younger or premenopausal patients are associated with poorer prognosis.

Premenopausal patients have higher estrogen levels than those in older (postmenopausal) patients. Estrogen is known to suppress anti-tumor T cell response and leading to tumor progression in different animal models (Clin Cancer Res 2016 22:6204), including lung cancer, melanoma, ovarian cancer. One of the mechanisms that contributes to estrogen's suppression of T cell function is via the mobilization of myeloid-derived suppressor cells (MDSC). Targeting ER signaling with hormonal therapy can abolish MDSC mobilization, and sensitize tumor cells to antigen specific T cell or NK cell killing (Cancer Discovery 2018 7:72 2017). These study results further support the hypothesis that, E2 is associated with immunosuppressive effect, and may contribute to the suppression of immune surveillance in young female breast cancer patients. These results suggest that E2 may suppress anti-tumor immunity, and E2 reduction improve the anti-tumor immunity. In our preliminary works, the investigators found higher dose (equivalent to premenopausal women serum level) of E2 suppressed T cell activities, while lower dose E2 (postmenopausal serum level) activated T cell activity. The investigators have investigated the combination of anti-PD1 antibody and GnRH agonist plus exemestane (an aromatase inhibitor which will block the production of E2 from adipose tissue) in ER positive premenopausal breast cancer patient refractory to prior endocrine therapy in metastatic setting. The response rate was 38.4%, and median progression-free survival (PFS) was 10.2 months. This outstanding result were presented in AACR 2021 oral session (Cancer Res 2021 81:13_Supplement, CT028). On the other hand, progesterone is also well known for its anti-inflammation and immune tolerance activity. This possibly makes estrogen reduction treatments, such as gonadotropin-releasing hormone agonist (GnRH agonist), an important partner in augmenting neoadjuvant therapy for patients with premenopausal breast cancer.

For triple negative breast cancer (TNBC), endocrine therapy has no anti-tumor effect. On the other hand, the use of GnRH agonist has been tested for the protection of ovary function of young female while receiving adjuvant chemotherapy. Surprisingly, the concomitant use of goserelin and adjuvant chemotherapy improved disease-free survival (HR 0.47, P=0.04) and overall survival (HR 0.45, P=0.05) versus chemotherapy alone in ER negative premenopausal early BC patients in POEMS study, which was initially aimed to improve the success pregnant rate (N Engl J Med 2015 372;923). Endocrine therapy is theoretically antagonist to chemotherapy therapy when concomitantly use. In another report analyzed the outcome of both pre- and postmenopausal women who entered two randomized trials (Gruppo Oncologico Nord-Ovest-Mammella Intergruppo studies) on adjuvant chemotherapy and received either concomitant or sequential hormonal therapy. The result showed a decreasing trend (P = 0.015) in hazard ratio of death with increasing age was observed, indicating that concomitant therapy is more effective than sequential therapy in young patients (Annals of Oncology 2008;19(2):299-307). These results support the hypothesis that, E2 suppression/ER inhibition therapy may modulate immune microenvironment, thereby enhancing the chemotherapy induced immunogenic death effect.

The investigators hypothesized that, estrogen level reduction by ovarian function suppression can modulate immune microenvironment, thereby augmenting adjuvant chemotherapy efficacy, regardless of the estrogen receptor (ER) status of cancer cell. Therefore, the investigators plan to test this hypothesis in real clinical model, with standard clinical recommended treatment doses.

The study is designed to evaluate whether the GnRH agonist can provide the therapeutic benefit for premenopausal TNBC patients via modulating immune microenvironment. Premenopausal TNBC patients will receive GnRH agonist and neoadjuvant chemotherapy, and the efficacy and immune microenvironment change of co-administration arm will be measured and compared with chemotherapy alone control arm.

Neoadjuvant Chemotherapy With or Without GnRH Agonist for Premenopausal Triple-negative Early Breast Cancer Patients

A Randomized Phase II Study of Neoadjuvant Chemotherapy With or Without GnRH Agonist for Premenopausal Triple-negative Early Breast Cancer Patients: ESCALATE Study

No invasive residual in breast or nodes; non-invasive breast residuals allowed

To compare the event-free survival (EFS) assessed by investigator in ITT population after neoadjuvant chemotherapy with/without ovary suppression

Quality of life will be assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 , the minimum values is : 30 , the maximum values is : 126, the higher scores mean a worse outcome

Follicle stimulating hormone (FSH) mIU/mL

To evaluate the tumor-infiltrating lymphocytes (TIL)

To evaluate the rate of pCR (ypT0/Tis ypN0) as assessed by the local pathologist at the time of definitive surgery in individuals with TIL(+) or TIL(-) tumors.

To evaluate Residual Cancer Burden (RCB) as assessed by the local pathologist at the time of definitive surgery

To determine the safety and tolerability of ovarian function suppression in combination with neoadjuvant chemotherapy in locally advanced TNBC subjects

Breast cancer quality of life will be assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire BR23 , the minimum values is : 22 , the maximum values is : 92, the higher scores mean a worse outcome

To evaluate the event free survival by investigator in individuals with TIL(+) or TIL(-) tumors.

Ministry of Health and Welfare

Debiopharm International SA

National Taiwan University Hospital

Leuprolide acetate

Sonya Kashyap, MD MSc

The purpose of this study is to determine whether gonadotropin releasing hormone agonists (medical therapy) will protect against ovarian failure in reproductive aged women undergoing sterilizing chemotherapy.

Fertility preservation is defined as the maintenance of one's ability to reproduce.

The hypothesis for this study is that medical treatment (GnRHa) will help female cancer patients, receiving sterilizing chemotherapy, preserve their ovarian function and therefore fertility. This study is a feasibility trial of the drug (GnRHa)vs placebo in female cancer patients receiving gonadotoxic chemotherapy between the ages of 18 and 38 who wish to participate.

The objective of the feasibility trial is to determine the feasibility of a definitive study to answer this question and also to define the required parameters needed to design the definitive study such as the observable difference in ovarian failure between the drug and placebo groups. The same protocol will be followed as proposed for the definitive trial but with a smaller sample size.

This pilot study will be conducted at the Ottawa Hospital Regional Cancer Centre/Division of Reproductive Medicine of Department of Obstetrics and Gynecology, University of Ottawa and the Cancer Centre of Southeastern Ontario/Division of Reproductive Medicine of Department of Obstetrics and Gynecology, University of Ottawa.

The planned trial intervention is trimonthly (every 3 months) administration of depot GnRHa (Leuprolide acetate (LA) 11.25 mg intramuscularly) or placebo. Injections would start prior to initiation of chemotherapy, in the luteal phase of the menstrual cycle preceding chemotherapy, and will continue until cessation of chemotherapy (maximum of 6 months or 2 injections). Since only adjuvant/curative chemotherapy patients will be enrolled, chemotherapy will last a maximum of six months.

Subjects will be randomized, with concealed allocation, to either GnRHa or placebo. Subjects and investigators will be blinded to the intervention administered.

Inclusion criteria: Women who are

1. between ages 18 to 38;
2. who will be undergoing gonadotoxic (sterilizing) curative/ adjuvant chemotherapy for early stage disease; and
3. have provided informed consent. All subjects will be enrolled from the Ottawa Hospital Regional Cancer Institute (OHRCC) and the Cancer Center of South Eastern Ontario at Kingston General Hospital (CCSEO). Gonadotoxic chemotherapy includes alkylating / anthracycline agents eg. cyclophosphamide.

Exclusion criteria: Women who;

1. have advanced stage disease and/or whose median survival is expected to be less than 6 months
2. have cancer of the ovaries, uterus, or fallopian tubes;
3. have clinical or biochemical evidence of diminished ovarian reserve (recent shortening of cycles \&lt; 24 days between menses, age \&gt; 38, elevated serum FSH (follicular stimulating hormone)\&gt; 15 IU/L, or low antral follicle count (AFC- number of follicles less than 10 mm on day 2 or 3 of natural menses) on baseline pelvic ultrasound (\&lt;5) or elevated day 2 or 3 estradiol (\&gt; 280 pmol/ml);
4. have previously received chemotherapy or abdominal/pelvic radiation or have planned to receive abdomino/pelvic radiation;
5. are pregnant;
6. have contraindications to intramuscular injections; or 7) have a history of fractures secondary to/or documented osteoporosis.

Outcomes: Subjects will be assessed at baseline, monthly (for adverse effects only) during active intervention, and at 0, 3, 6, 9, and 12 months post cessation of chemotherapy and treatment (GnRHa/ placebo) for predictors of ovarian reserve.

The primary outcome is protection against ovarian failure at 12 months post chemotherapy. This is measured by resumption of regular menstrual cycles (every 24 -35 days) with documentation of ovulation by biochemistry (progesterone levels) over a minimum of three months.

Secondary outcomes will include sonographic (biophysical) and biochemical markers of ovarian reserve.

PROtecting Ovaries and Fertility During Chemotherapy - The PROOF Trial

PROtecting Ovaries and Fertility During Chemotherapy - The PROOF Trial: A Randomized Controlled Trial of Gonadotropin Releasing Hormone Agonist (GnRHa) for Fertility Preservation in Oncology Patients

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Neoadjuvant Chemotherapy With or Without GnRH Agonist for Premenopausal Triple-negative Early Breast Cancer Patients	NCT06225284	Triple Negative... Premenopausal B...	Goserelin Aceta...	18 Years - 50 Years	National Taiwan University Hospital
PROtecting Ovaries and Fertility During Chemotherapy - The PROOF Trial	NCT00380406	Fertility Prese... Cancer	Leuprolide acet...	18 Years - 38 Years	Ottawa Hospital Research Institute

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