Breast: intensify endocrine therapy and keep adherence

A 44-year-old nurse has finished chemotherapy and radiotherapy for hormone receptor-positive, HER2-negative breast cancer. The tumor was 3.5 centimeters, grade 3, and there was metastasis in 5 axillary lymph nodes. She started tamoxifen two months ago and already complains of hot flashes and insomnia. At the visit, she hears that there are options to reduce the risk even further: ovarian suppression, a switch to an aromatase inhibitor and a new pill for two or three years. She asks whether all of this is necessary and admits she has already thought about stopping tamoxifen. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The question comes from Dr. Alexei's list for the oncology series: when to intensify adjuvant endocrine therapy in breast cancer, and how to make sure the patient can take it for years? The reference trials are monarchE, with abemaciclib, NATALEE, with ribociclib, the SOFT and TEXT trials, with ovarian suppression, and the adherence studies. The text does not replace your country's guideline or your service's protocol. If you play the case of the day on NEXO, you will recognize the challenge: the best treatment is the one the patient can follow.

Key points

• Adjuvant endocrine therapy lasts at least 5 years, and adherence falls every year.
• In high-risk premenopause, ovarian suppression plus tamoxifen or an aromatase inhibitor reduces recurrence, with more adverse effects.
• monarchE showed that 2 years of abemaciclib reduce invasive recurrence in patients with involved lymph nodes and high risk.
• NATALEE showed a gain with 3 years of ribociclib in a broader population, including stage II.
• Each intensification adds toxicity, cost and visits, which weigh on adherence.
• Asking about adverse effects and treating them is part of the treatment, not a detail.

Why this is a reasoning scenario

In hormone receptor-positive breast cancer, recurrence can appear many years after diagnosis. Adjuvant endocrine therapy reduces this risk, but it only works if it is taken. That is why the decision to intensify treatment cannot be separated from the question about adherence.

In recent years, the options for intensification have multiplied. Ovarian suppression already had a place in premenopause. CDK4 and CDK6 inhibitors, previously used only in metastatic disease, now have data in the adjuvant setting. Each option adds benefit for a specific group and adds adverse effects for every patient who receives it.

The nurse's scenario brings together both sides of the problem. She is at high risk because of the number of lymph nodes and the grade. At the same time, she already has symptoms with tamoxifen and has already thought about stopping. Intensifying without addressing the symptoms can lead to stopping everything. The post about who decides the treatment sequence in breast cancer shows how the team organizes these decisions.

The mistake the scenario wants to avoid

The most common mistake is treating adherence as the patient's problem rather than the team's. When the doctor prescribes and only asks again the following year, silent interruption goes unnoticed. Another mistake is intensifying treatment in someone at low risk, exposing the patient to adverse effects with little gain.

Ovarian suppression in premenopause

In premenopausal women, the ovaries are the main source of estrogen. Ovarian suppression, done with gonadotropin-releasing hormone analogs such as goserelin, reduces this estrogen and allows the use of aromatase inhibitors, which do not work on their own at this stage of life.

What the SOFT and TEXT trials showed

In the subgroup of women under 35 years of age in the SOFT study, 5-year breast cancer-free survival was 67.7 per 100 with tamoxifen alone and 78.9 per 100 with tamoxifen and ovarian suppression (Yan et al., 2015). This finding helps explain why suppression is discussed more in young, high-risk women (Yan et al., 2015). The combination of exemestane with ovarian suppression was tested in the pooled analysis of the TEXT and SOFT studies (Yan et al., 2015).

The price of suppression

In SOFT, hot flashes, sweating, loss of libido, vaginal dryness, insomnia, depression, musculoskeletal symptoms, hypertension and glucose intolerance were more frequent with ovarian suppression (Ozaki et al., 2018). Grade 3 or higher adverse events occurred in 31.3 per 100 women on suppression plus tamoxifen, versus 23.7 per 100 on tamoxifen alone (Ozaki et al., 2018). Non-adherence to suppression rose from 9.2 per 100 in the first year to 21.9 per 100 in the fourth year (Ozaki et al., 2018).

A small substudy found no significant cognitive decline with ovarian suppression compared with tamoxifen alone (Phillips et al., 2016). This finding helps answer a frequent patient question, but it comes from 74 women and must be read with caution (Phillips et al., 2016).

When suppression fails

Up to 20 per 100 premenopausal women receiving an analog with an aromatase inhibitor may have inadequate ovarian suppression, with estradiol above the expected level (Valenza et al., 2026). In these cases, the aromatase inhibitor stops working, and periodic estradiol measurement helps detect the problem (Valenza et al., 2026).

monarchE: abemaciclib for two years

monarchE was an open-label phase III study with 5,637 patients with hormone receptor-positive, HER2-negative breast cancer and high-risk involved lymph nodes (Johnston et al., 2020). Enrolled patients had 4 or more involved lymph nodes, or 1 to 3 lymph nodes and at least one of these factors: tumor of 5 centimeters or more, grade 3, or central Ki-67 of 20 or more (Johnston et al., 2020).

Dose and duration

Patients were randomized to standard endocrine therapy with or without abemaciclib 150 mg twice a day for 2 years (Johnston et al., 2020). Endocrine therapy continued for at least 5 years (Rastogi et al., 2024). Check the package insert in your country before prescribing.

Results

In the analysis with a median follow-up of 54 months, abemaciclib reduced the risk of an invasive disease-free survival event, with a hazard ratio of 0.680 (Rastogi et al., 2024). The absolute gain increased over time, reaching 7.6 points at 5 years, versus 6 points at 4 years and 4.8 points at 3 years (Rastogi et al., 2024). There were fewer deaths in the abemaciclib group, 208 versus 234, but the overall survival difference did not yet have statistical significance in this analysis (Rastogi et al., 2024).

The benefit was consistent in premenopause and postmenopause. In premenopausal women, the absolute gain at 3 years was 5.7 points in invasive disease-free survival (Paluch-Shimon et al., 2023).

Toxicity and dose reductions

The most frequent adverse events with abemaciclib were diarrhea, neutropenia and fatigue, and venous thrombosis occurred in 2.3 per 100 patients, versus 0.5 per 100 in the control group (Johnston et al., 2020). Of the 2,791 patients treated with abemaciclib, 43.7 per 100 needed a dose reduction, mainly for diarrhea (Goetz et al., 2024). The analyses showed that the benefit was maintained with the dose reduced to 100 mg or 50 mg (Goetz et al., 2024). This finding is useful in the conversation with the patient, because reducing the dose to keep the treatment going is better than stopping it.

Study	Drug and dose	Duration	Population	Main result	Source
monarchE	Abemaciclib 150 mg twice a day	2 years	High-risk involved lymph nodes	Absolute gain of 7.6 points at 5 years	Rastogi et al., 2024
NATALEE	Ribociclib 400 mg per day, 21 of 28 days	3 years	Selected stage IIA, IIB and III	Absolute gain of 4.9 points at 4 years	Fasching and colleagues, 2025
SOFT, under 35 years	Tamoxifen with ovarian suppression	5 years	Premenopause	Breast cancer-free survival of 78.9 versus 67.7 per 100	Yan and colleagues, 2015

NATALEE: ribociclib for three years

NATALEE was an open-label phase III study that included women at any menopausal stage and men with hormone receptor-positive, HER2-negative breast cancer in selected stage IIA, IIB and III (Slamon and colleagues, 2023). Stage IIA could have no involved lymph nodes, as long as there were additional risk factors, or 1 to 3 lymph nodes (Fasching and colleagues, 2025).

Dose and duration

Patients received ribociclib 400 mg once a day, on days 1 to 21 of 28-day cycles, for 36 months, with letrozole 2.5 mg or anastrozole 1 mg per day for 60 months (Fasching and colleagues, 2025). Men and premenopausal women also received goserelin (Fasching and colleagues, 2025). Check the package insert in your country before prescribing.

Results

In the 4-year analysis with 5,101 patients, ribociclib kept its benefit in invasive disease-free survival, with a hazard ratio of 0.72 (Fasching and colleagues, 2025). The 4-year rate was 88.5 per 100 with ribociclib and 83.6 per 100 without it, a difference of 4.9 points (Fasching and colleagues, 2025). Overall survival was still immature, with a hazard ratio of 0.83 and an interval that included 1 (Fasching and colleagues, 2025).

Toxicity

The most frequent adverse events with ribociclib were neutropenia, arthralgia and nausea, and liver changes were mostly transaminase increases without bilirubin increase (Fasching and colleagues, 2025). QT interval prolongation occurred in 5.4 per 100 patients with ribociclib and in 1.6 per 100 without it (Fasching and colleagues, 2025). This requires an electrocardiogram and a review of medicines that also prolong the QT.

Who is high risk

The two studies defined high risk differently, and this difference has a practical consequence. In a cohort with 4,795 patients, 28 per 100 would be high risk by the monarchE criteria and 56.1 per 100 by the NATALEE criteria (Arecco and colleagues, 2025). Disease-free survival at 7 years was 69 per 100 in patients at high risk by both criteria, versus 89 per 100 in those at low risk by both (Arecco and colleagues, 2025).

In a French registry with 3,103 patients treated between 2005 and 2015, 14.2 per 100 would be eligible for abemaciclib by the monarchE criteria (Ladoire and colleagues, 2025). These numbers show that the choice of criteria greatly changes the number of patients exposed to an expensive treatment with adverse effects.

Applying the criteria to the scene

The nurse in the scene has 5 involved lymph nodes, which places her in the monarchE high-risk group, which required 4 or more lymph nodes or 1 to 3 with additional factors (Johnston and colleagues, 2020). She would also meet the NATALEE criteria, which included stage III (Slamon and colleagues, 2023). Because she is premenopausal, either regimen would require ovarian suppression, as was done in the studies. The choice between them depends on practical factors, such as the risk of diarrhea, liver function, the electrocardiogram, access to the medicine and the patient's preference, since there is no direct comparison between the two.

Questions to decide on intensification

• How many lymph nodes were involved and what was the tumor size?
• What was the grade and, when available, the Ki-67?
• Is the patient premenopausal or postmenopausal?
• Does she have comorbidities that increase the risk of diarrhea, neutropenia, thrombosis or arrhythmia?
• Does she use medicines that interact or prolong the QT?
• Does she already have adverse effects with the current endocrine treatment?
• Can the service perform blood tests and electrocardiograms as often as needed?

Adherence as a clinical outcome

Intensification studies show gains of a few points. Those gains disappear if the patient does not take the medication. That is why adherence needs to be treated as a clinical outcome, measured and tracked.

The size of the problem

In a systematic review of 26 studies, mean adherence at 5 years was 66.2 per 100 patients, and persistence was 66.8 per 100 (Yussof et al., 2022). On average, adherence fell 25.5 points from the first to the fifth year (Yussof et al., 2022). In Scotland, in a cohort of 3,361 women, adherence below 80 per 100 days of treatment was associated with worse survival, with a hazard ratio of 1.20 (Makubate et al., 2013).

How to measure it

In a Spanish cohort of 692 women, adherence ranged from 92 per 100 by patient report to 94.7 per 100 by physician report, but agreement between the measures was low (Font et al., 2012). Persistence at 5 years was 74.7 per 100, and women under 50 adhered less (Font et al., 2012). Self-report alone tends to overestimate adherence, and the systematic review confirmed that adherence is higher when measured by self-report than by dispensing records (Yussof et al., 2022).

Signs that the patient may be stopping

• Vague answers when asked how she is taking the pill.
• Prescriptions renewed at longer intervals than expected.
• Repeated complaints of joint pain, hot flashes or untreated insomnia.
• New depressive symptoms or worsening mood.
• Missed appointments or missed follow-up tests.

None of these signs confirms discontinuation, but each one justifies an honest conversation. Patients usually tell the truth when they sense the team wants to help and not judge. Asking "how many pills did you forget last week?" works better than "are you taking it properly?", because the first question allows an honest answer.

In the nurse's scenario, the confession that she thought about stopping is an opportunity. Before discussing ovarian suppression or a CDK4 and CDK6 inhibitor, the team needs to treat the hot flashes and insomnia and explain why tamoxifen matters. Only then does it make sense to add a treatment that will bring new adverse effects.

Why patients stop

In an online survey of 2,353 women and 54 men, 91.2 per 100 reported adverse effects of endocrine treatment, and about one third stopped treatment earlier than planned (Berkowitz et al., 2021). In the same survey, 31.5 per 100 felt the adverse effects were minimized by the team (Berkowitz et al., 2021). The systematic review identified depression, comorbidities and adverse effects as factors associated with lower adherence (Yussof et al., 2022).

How to keep the patient on treatment

Adherence improves when the team treats symptoms, explains the reason for treatment and keeps in regular contact. There is no single intervention that solves the problem, but some have evidence.

Information and contact

In a randomized study with an aromatase inhibitor, adherence at 12 months was 48 per 100 in the control group, 62.7 per 100 in the group with telephone contact and 64.7 per 100 in the group that received informational letters (Ziller et al., 2013). The pooled analysis showed a significant difference in favor of the interventions (Ziller et al., 2013).

Treating joint pain

Joint pain from aromatase inhibitors is one of the most frequent causes of discontinuation. In a study of 253 women with this symptom, 26.9 per 100 stopped treatment, and combining more than one management strategy, such as analgesic, physical therapy or regimen adjustment, was associated with fewer discontinuations in patients with severe pain (Liang et al., 2026).

Practical strategies

• Ask at every visit, directly, how many pills the patient has missed.
• Investigate and treat hot flashes, insomnia, joint pain and vaginal dryness.
• Offer a change of medication before the patient gives up on her own.
• Reduce the dose of CDK4 and CDK6 inhibitors when necessary, instead of suspending them.
• Track depression and refer for psychological support.
• Agree on a contact channel between visits.

The post on diagnostic uncertainty helps with conversations about small benefits and known risks.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. Endocrine intensification is a good exercise because the decisive clue may be in the history, such as silent discontinuation of tamoxifen, and not in the report. The post on differential diagnosis with clues shows how to train with progressive clues.

Three exercises with cases

Change the risk. Say what changes if the patient has a 2.5-centimeter, grade 2 tumor and no involved lymph nodes.

Change the menopause. Say how to choose the regimen if the patient is 62 years old and has osteoporosis.

Change adherence. Say what to do if, in the sixth month of abemaciclib, the patient reports daily diarrhea and admits she skipped several doses.

The post on clinical decision-making deals with choices with small benefit. The limits on using the game are on the NEXO economy page. If you research teaching of clinical reasoning, the page for researchers explains how to get in touch.

Frequently asked questions

What is the abemaciclib dose in monarchE?

Abemaciclib 150 mg twice a day for 2 years, with standard endocrine therapy (Johnston et al., 2020). Check the package insert in your country before prescribing.

What is the ribociclib dose in NATALEE?

Ribociclib 400 mg once a day, on days 1 to 21 of 28-day cycles, for 36 months, with letrozole or anastrozole (Fasching et al., 2025). Check the package insert in your country before prescribing.

Does abemaciclib dose reduction compromise the benefit?

No, according to the monarchE analyses, which showed consistent benefit with 150 mg, 100 mg or 50 mg (Goetz et al., 2024).

Does every premenopausal woman need ovarian suppression?

No. The greater gain appeared in young, high-risk women, and suppression brings more adverse effects (Yan et al., 2015) (Ozaki et al., 2018).

Does low adherence really increase the risk?

Yes. In a Scottish cohort, adherence below 80 out of every 100 days of treatment was associated with higher mortality (Makubate et al., 2013).

Final checklist

• I classified the risk by lymph nodes, size, grade and Ki-67.
• I defined menopausal status with objective criteria.
• I discussed ovarian suppression in young high-risk women.
• I assessed eligibility for abemaciclib or ribociclib.
• I ordered baseline tests, including blood count, liver function and electrocardiogram when indicated.
• I asked about adverse effects and adherence at every visit.
• I agreed on a contact channel between visits.
• I planned the total duration of endocrine therapy.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. Arecco L, Blondeaux E, Bruzzone M, et al. Prognostic implications of risk definitions from the monarchE and NATALEE trials. J Natl Cancer Inst. 2025. PMID 39908473.
2. Berkowitz MJ, Thompson CK, Zibecchi LT, et al. How patients experience endocrine therapy for breast cancer: an online survey of side effects, adherence, and medical team support. J Cancer Surviv. 2021. PMID 32804353.
3. Fasching PA, Stroyakovskiy D, Yardley DA, et al. Ribociclib Plus Endocrine Therapy in Hormone Receptor-Positive/ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial. JAMA Oncol. 2025. PMID 40996773.
4. Font R, Espinas JA, Gil-Gil M, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. Br J Cancer. 2012. PMID 22955858.
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8. Liang M, Yuan S, Xue Y, et al. Management Strategies for Aromatase Inhibitor-Associated Musculoskeletal Symptoms and Their Impact on Treatment Persistence in Postmenopausal Breast Cancer: A Single-Center Retrospective Cohort Study. Int J Womens Health. 2026. PMID 42221428.
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10. Ozaki Y, Tanabe Y, Tamura N, et al. Impact on disease-free survival of the duration of ovarian function suppression, as postoperative adjuvant therapy, in premenopausal women with hormone receptor-positive breast cancer: a retrospective single-institution study. Breast Cancer. 2018. PMID 29357022.
11. Paluch-Shimon S, Neven P, Huober J, et al. Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2-, node-positive, high-risk early breast cancer. Ther Adv Med Oncol. 2023. PMID 36756142.
12. Phillips KA, Regan MM, Ribi K, et al. Adjuvant ovarian function suppression and cognitive function in women with breast cancer. Br J Cancer. 2016. PMID 27092785.
13. Rastogi P, O'Shaughnessy J, Martin M, et al. Adjuvant Abemaciclib Plus Endocrine Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, High-Risk Early Breast Cancer: Results From a Preplanned monarchE Overall Survival Interim Analysis, Including 5-Year Efficacy Outcomes. J Clin Oncol. 2024. PMID 38194616.
14. Slamon DJ, Fasching PA, Hurvitz S, et al. Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer. Ther Adv Med Oncol. 2023. PMID 37275963.
15. Valenza C, Etessami JD, Milano M, et al. Inadequate ovarian function suppression and endocrine therapy manipulations in premenopausal patients with early breast cancer on adjuvant LHRH agonist and aromatase inhibitor: a cohort study. ESMO Open. 2026. PMID 41650747.
16. Yan S, Li K, Jiao X, et al. Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials. Onco Targets Ther. 2015. PMID 26109867.
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18. Ziller V, Kyvernitakis I, Knöll D, et al. Influence of a patient information program on adherence and persistence with an aromatase inhibitor in breast cancer treatment--the COMPAS study. BMC Cancer. 2013. PMID 24006873.