What is the preferred treatment regimen for this female patient?

Preferred Treatment Regimen for Female Patients with Hormone Receptor-Positive Advanced Breast Cancer

Primary Recommendation

For premenopausal women with hormone receptor-positive advanced breast cancer, the preferred first-line treatment is ovarian function suppression/ablation (OFS/OFA) combined with an aromatase inhibitor (AI) plus a CDK 4/6 inhibitor, which provides superior progression-free survival with an acceptable toxicity profile. 1

Treatment Algorithm by Menopausal Status

For Premenopausal/Perimenopausal Women

Ovarian suppression is mandatory - premenopausal women with ER-positive advanced breast cancer should have adequate OFS/OFA and then be treated in the same way as postmenopausal women, with endocrine agents with or without targeted therapies. 1

First-Line Endocrine Therapy Options (in order of preference):

1. OFS/OFA + AI + CDK 4/6 inhibitor (preferred for moderate-to-high risk patients)

   • This combination provided a significant improvement in median PFS of 10 months with acceptable toxicity and is one of the preferred treatment options. 1
   • OS results are still awaited, but quality of life was comparable to endocrine therapy alone. 1

2. OFS/OFA + AI alone (if CDK 4/6 inhibitor not available or appropriate)

   • The preferred first-line endocrine therapy depends on the type and duration of adjuvant endocrine therapy and time elapsed from the end of adjuvant therapy; it can be an AI, tamoxifen, or fulvestrant. 1

3. OFS/OFA + Tamoxifen (alternative option)

   • Tamoxifen combined with ovarian suppression is the preferred first-line treatment for premenopausal women, demonstrating superior efficacy compared to either treatment alone. 2
   • This combination is preferred if the patient has not received prior adjuvant tamoxifen or if tamoxifen was discontinued more than 12 months ago. 2

4. Single-agent tamoxifen (only if patient declines OFS/OFA)

   • This is the only available endocrine option for premenopausal women who decline OFS/OFA, but it is a less effective option. 1

Methods of Ovarian Suppression

Laparoscopic bilateral oophorectomy ensures definitive estrogen suppression and contraception, avoids potential initial tumor flare with LHRH agonist, and may increase eligibility for clinical trials. 1

LHRH agonists are an acceptable alternative to surgical oophorectomy with similar outcomes in metastatic disease. 2

Patients should be informed on the options of OFS/OFA and decisions should be made on a case-by-case basis. 1

For Postmenopausal Women

First-Line Treatment:

AI + CDK 4/6 inhibitor is the preferred treatment option for postmenopausal women, providing significant improvement in median PFS (10 months) with acceptable toxicity. 1

Alternative first-line options include:

• AI alone 1
• Tamoxifen 1
• Fulvestrant 1

Second-Line and Subsequent Therapy

If CDK 4/6 Inhibitor Not Previously Used:

Fulvestrant + CDK 4/6 inhibitor is one of the preferred treatment options in patients previously exposed to endocrine therapy, providing significant improvement in median PFS (6-7 months) as well as improvement in quality of life. 1

If CDK 4/6 Inhibitor Previously Used:

Exemestane + everolimus is a valid option for patients previously exposed to endocrine therapy, since it significantly prolongs PFS, albeit without evidence of OS benefit. 1

Important caveat: Adequate prevention, close monitoring, and proactive treatment of adverse events is needed, particularly in older patients treated with everolimus due to the increased incidence of toxic deaths reported in the BOLERO-2 trial. 1

Critical Treatment Principles

When to Use Endocrine Therapy vs. Chemotherapy:

Endocrine therapy is the preferred option for HR-positive disease, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance. 1

Concomitant chemotherapy and endocrine therapy has not shown a survival benefit and should not be carried out outside a clinical trial. 1

Duration of Treatment:

Usually each regimen (except anthracyclines) should be given until progression of disease or unacceptable toxicity. 1

What is considered unacceptable should be defined together with the patient. 1

Common Pitfalls to Avoid

1. Do not use aromatase inhibitors in premenopausal women without adequate ovarian suppression - aromatase inhibitors are contraindicated in premenopausal women without adequate ovarian suppression, as reduced tissue estrogen can cause compensatory rises in ovarian estrogens. 2

2. Significant caution is required when using GnRH agonists with aromatase inhibitors - ovarian suppression may be incomplete, leading to continued ovarian estrogen production. 2

3. Do not use tamoxifen simultaneously with chemotherapy - concurrent use is detrimental; endocrine therapy should be initiated after completion of chemotherapy if chemotherapy is indicated. 2

4. Do not overlook fertility preservation discussions - providers should recognize and acknowledge loss of fertility as a specific issue faced by premenopausal women with metastatic breast cancer, and options such as cryopreservation of embryos or oocytes should be discussed. 2