Optimal Endocrine Therapy for Premenopausal Women with Breast Cancer
Endocrine therapy is a cornerstone of treatment for hormone receptor-positive breast cancer in premenopausal women. However, the optimal treatment approach remains complex and nuanced. Aromatase inhibitors (AIs) are highly effective in postmenopausal women, but their use in premenopausal women requires ovarian function suppression (OFS) to mitigate ovarian estrogen production. Recent studies support the combination of OFS and AIs as a preferred regimen for high-risk premenopausal patients, offering improved invasive disease-free survival and overall survival. However, treatment decisions must consider individual patient factors, including life stage, future family planning desires, and management of side effects. This review discusses the current landscape of endocrine therapy in premenopausal women with hormone receptor-positive breast cancer, highlighting the importance of personalized care plans and ongoing monitoring and support.
Patient: Doctor, I’m a 54-year-old woman and I’ve just been diagnosed with breast cancer. I underwent a breast-sparing mastectomy and I’m still trying to process everything.
Doctor: I understand. Let’s go over the details of your diagnosis. The tumor margin did not show any invasion, which is good news. The sentinel axillary lymph node biopsy was also negative for nodal metastasis.
Patient: That’s a relief. But what about the tumor itself? What did the tests show?
Doctor: The tumor was estrogen receptor and progesterone receptor positive, but HER-2 negative. This means that hormone therapy could be an effective treatment option for you.
Patient: Okay, that makes sense. You started me on tamoxifen. How will that help?
Doctor: Tamoxifen is a selective estrogen receptor modulator (SERM) that can help block the effects of estrogen on breast cancer cells. It’s often used to treat hormone receptor-positive breast cancer.
Patient: I’ve been experiencing some side effects since starting the tamoxifen. I get hot flashes that come and go in waves and they’re affecting my sleep significantly.
Doctor: I’m not surprised. Hot flashes are a common side effect of tamoxifen. As a result of this therapy, you may also experience vaginal dryness, mood changes, and changes in your menstrual cycle.
Patient: That’s helpful to know. Are there any other potential side effects I should be aware of?
Doctor: Yes, there are. Tamoxifen can also increase your risk of endometrial cancer, so we’ll need to monitor you closely for any signs of that. Additionally, some women experience changes in their lipid profiles and may be at increased risk for stroke and blood clots.
Patient: I see. It’s a lot to take in, but I appreciate your honesty. What can I do to manage these side effects?
Doctor: We can discuss some strategies for managing hot flashes and other side effects. There are also some medications that can help alleviate these symptoms. Let’s work together to find a plan that works for you.
Optimal Endocrine Therapy for Premenopausal Women with Breast Cancer
Suppressing estrogen levels in postmenopausal women is a critical strategy in managing estrogen receptor-positive (ER+) breast cancer, primarily through the use of aromatase inhibitors (AIs) and selective estrogen receptor degraders (SERDs). Aromatase inhibitors, such as letrozole, anastrozole, and exemestane, are highly effective in postmenopausal women as they significantly reduce estrogen synthesis by inhibiting the aromatase enzyme, which is responsible for converting androgens to estrogens in peripheral tissues(Paul & Sudandiradoss, 2015) (Schneider et al., 2011). These inhibitors have surpassed tamoxifen as the first-line therapy for postmenopausal women with metastatic, hormone receptor-positive breast cancer, offering improved response rates and time to progression(Schneider et al., 2011). In contrast, their efficacy as monotherapy in premenopausal women is limited due to the upregulation of ovarian aromatase in response to gonadotropins, which maintains estrogen production despite AI treatment(Elnahhas & M, 2010). In premenopausal women, combining ovarian function suppression (OFS) with AIs or antiestrogens like tamoxifen is necessary to achieve adequate estrogen suppression, although the clinical outcomes of such combinations can be variable(Dowsett et al., 2016).
In premenopausal women with hormone receptor-positive breast cancer, the effectiveness of aromatase inhibitors (AIs) is limited due to the upregulation of ovarian aromatase in response to gonadotropins, necessitating the use of gonadotropin-releasing hormone agonists (GnRHas) to suppress ovarian function. This approach is crucial because ovarian suppression can significantly reduce estrogen production, which is vital for the growth of estrogen receptor-positive tumors(LeVasseur et al., 2024) (Francis, 2023). Clinical trials, such as the SOFT and TEXT trials, have demonstrated the survival benefits of combining ovarian function suppression (OFS) with GnRHas and AIs in high-risk premenopausal patients, showing a significant reduction in breast cancer recurrence and mortality(Gomes et al., 2023)(Gray et al., 2023). GnRHas like goserelin are effective in achieving this suppression, with studies indicating that 3-monthly administration of goserelin is more effective than monthly administration in maintaining low estradiol levels, thus enhancing the efficacy of AIs(Gomes et al., 2023). Moreover, the use of GnRHas during chemotherapy has been shown to protect ovarian function, reducing the risk of premature ovarian failure and preserving fertility, which is a significant concern for young women undergoing cancer treatment(Li, 2022) (Poggio et al., 2019) (Abdel-Razeq, 2019). Despite the benefits, the choice between GnRHas combined with tamoxifen or AIs remains complex, with considerations for patient-specific factors such as risk of relapse and potential side effects(Conte et al., 2017)(Lambertini et al., 2017). Overall, the integration of GnRHas in the treatment regimen for premenopausal women with breast cancer is a strategic approach to enhance the effectiveness of AIs by mitigating the ovarian estrogen production that limits their efficacy(LeVasseur et al., 2024) (Francis, 2023) (Gray et al., 2023).
SERDs, such as GDC-0927, offer an alternative by degrading the estrogen receptor itself, showing promise in postmenopausal women with advanced ER+ breast cancer, including those with ESR1 mutations that confer resistance to traditional endocrine therapies(Dickler et al., 2018). The development of resistance to endocrine therapies remains a significant challenge, often due to mutations in the estrogen receptor gene (ESR1), necessitating the exploration of combination therapies and novel agents to maintain therapeutic efficacy(Nagaraj & Ma, 2015). Overall, while AIs and SERDs are effective in postmenopausal women, their use in premenopausal women requires additional strategies to suppress ovarian estrogen production effectively(Miller et al., 2007) (Lewis-Wambi & Jordan, 2005).
The optimal treatment schema for premenopausal women with breast cancer, particularly those with hormone receptor-positive tumors, involves a nuanced approach that balances efficacy with quality of life considerations. Recent studies emphasize the importance of ovarian function suppression (OFS) combined with aromatase inhibitors (AIs) as a cornerstone of adjuvant endocrine therapy for high-risk premenopausal patients. This combination has been shown to significantly improve invasive disease-free survival (iDFS) and overall survival (OS) compared to selective estrogen receptor modulators (SERMs) alone, particularly in women over 40 years old(“Optimal Endocrine Therapy in Premenopausal Women: A Pragmatic Approach to Unanswered Questions”, 2022) (Hu et al., 2019). Despite the benefits, the extended use of AIs beyond five years, although beneficial in postmenopausal women, lacks direct evidence in premenopausal populations, highlighting a need for further research(Buono et al., 2022). The NCCN guidelines recommend either AIs or tamoxifen with OFS for five years, but meta-analyses show no significant difference in disease-free survival or overall survival between these regimens, suggesting that both are viable options depending on individual patient factors(Meng et al., 2020). Additionally, the management of side effects such as menopausal symptoms, bone density loss, and fertility concerns is crucial, as these can impact treatment adherence and quality of life(Lambertini et al., 2023) (“Advances in the Management of Menopausal Symptoms, Fertility Preservation, and Bone Health for Women With Breast Cancer on Endocrine Therapy”, 2023). A multidisciplinary approach is essential to address these issues, alongside genetic counseling and fertility preservation, to ensure comprehensive care for premenopausal women with breast cancer(Parisi et al., 2020). The complexity of treatment decisions underscores the importance of personalized care plans that consider both the biological characteristics of the tumor and the personal circumstances of the patient, including their life stage and future family planning desires(Ono, 2023). Overall, while OFS plus AI is emerging as a preferred regimen, the choice of therapy should be tailored to the individual, with ongoing monitoring and support to manage the long-term implications of treatment(“Optimal Endocrine Therapy in Premenopausal Women: A Pragmatic Approach to Unanswered Questions”, 2022) (Hu et al., 2019) (Lambertini et al., 2023).
