Navigating Treatment Adherence in Early-Stage Breast Cancer

Background  

Hormone receptor–positive, HER2-negative (HR+ HER2-) breast cancer is the most common subtype. It accounts for approximately 70% of all breast cancer cases, with an age-adjusted rate of 91.3 new cases per 100,000 women based on data from 2018 to 2022.¹ The standard treatment for HR+ breast cancer typically involves endocrine therapy combined with surgery and radiation therapy. Over the past decade, CDK4/6 inhibitors have emerged as a critical addition to treatment regimens for patients with HR+ HER2- breast cancer, particularly for those with high-risk features.  

There are currently three U.S. Food and Drug Administration (FDA)–approved CDK4/6 inhibitors, but only two have shown statistical significance in improving outcomes for patients with early-stage breast cancer. This case report focuses on adjuvant ribociclib, which was approved by the FDA in September 2024 for use in patients with early-stage HR+ HER2- breast cancer who exhibit high-risk features, as demonstrated in the NATALEE trial.²  

The eligibility criteria for the NATALEE trial included both pre- and postmenopausal women and men with anatomic stages IIA, IIB, or III disease, all of whom had undergone surgical resection. Patients with stage IIA disease could be enrolled if they had N0 or N1 status or other high-risk features, such as grade 2 or 3 tumors. For those with stage IIA or N0 disease or with grade 2 tumors, evidence of high genomic risk was required—specifically a Ki-67 score of ≥ 20%, an Oncotype DX Breast Recurrence Score of ≥ 26, or MammaPrint high-risk scores. Patients with stage IIB disease or stage III disease (including N0 and N1) were eligible.²

In the 3-year final analysis of the NATALEE trial, the addition of ribociclib to aromatase inhibitors (AI) demonstrated a significant benefit in invasive disease–free survival (iDFS). At 3 years, the iDFS  was 90.7% in the ribociclib + AI group compared with 87.6% in the AI-alone group, reflecting an absolute difference of 3.1% and a 25.1% relative reduction in the risk of an iDFS event (HR = 0.749; 95% CI: 0.628–0.892). Post hoc analyses showed a 2.7% absolute difference at 3 years, a 4.9% absolute difference at 4 years, and a 28.5% reduction in the risk of iDFS events.³

Although ribociclib offers significant clinical benefits, it can be associated with potential side effects, including fatigue, nausea, vomiting, constipation, diarrhea, skin rash, neutropenia, QT prolongation, interstitial lung disease, and elevation of liver enzymes.   

Clinical Course  

A 37-year-old premenopausal woman was initially diagnosed with stage IIA pT2N0M0 left invasive ductal carcinoma (IDC) that was grade 3, estrogen receptor Allred score 8, progesterone receptor Allred score 2, HER2 non-amplified (2+ immunohistochemistry, FISH negative), and had a Ki67 of 30%. Her Oncotype DX score was 29, and genetic testing revealed a MSH3 variant of uncertain significance. She underwent bilateral mastectomies with sentinel lymph node biopsy and received adjuvant chemotherapy with docetaxel and cyclophosphamide for four cycles. Following chemotherapy, she started tamoxifen and goserelin as part of her definitive endocrine therapy regimen. However, her treatment was interrupted early due to poor tolerance, with symptoms including weight fluctuations, abdominal bloating, fatigue, lethargy, grogginess, and brain fog.  

Because of these intolerable side effects, she chose to discontinue conventional endocrine therapy and pursued an alternative approach involving integrative health therapies, while continuing surveillance with circulating tumor DNA (ctDNA) testing. Her initial ctDNA test was negative, but a subsequent monthly test became positive. Full restaging scans revealed no evidence of metastatic disease. However, indeterminate pulmonary nodules were noted, which were subsequently deemed likely benign granulomas, and a liver lesion was identified as a focal fatty infiltration. It is important to highlight that comprehensive staging scans did not reveal any discrete mass or overt signs of recurrence. Nonetheless, therapy was resumed based on the positive minimal residual disease (MRD) findings.  

After discussions regarding her treatment options, she agreed to restart endocrine therapy with monthly goserelin injections and letrozole 2.5 mg daily. Several months after resumption, adjuvant ribociclib in the early-stage setting received FDA approval based on the NATALEE trial results; therefore, standard-dose ribociclib (400 mg orally once daily, administered on a 21-day on/7-day off schedule) was added to her adjuvant regimen because she met treatment the criteria. Prior to initiation, guidelines were followed by obtaining a baseline electrocardiogram to ensure a Fridericia-corrected QT interval of < 450 milliseconds. Baseline laboratory studies were also collected and were within normal parameters, including a complete blood count (CBC), liver function tests (LFTs), and serum electrolytes (potassium, magnesium, calcium, and phosphorus). CBC, serum electrolytes, and LFTs were monitored every 2 weeks for the first two cycles, then at the start of every subsequent cycle or as clinically indicated. Follow-up ECGs were also performed on the first day of the second cycle, as well as on Day 14 of Cycles 1 and 2. The patient was also observed closely for clinical signs of dermatologic toxicity and for symptoms suggestive of interstitial lung disease or pneumonitis, including hypoxia, cough, and dyspnea.    

During the patient’s 2- and 4-week follow-up visits, she reported mild fatigue, nausea, and insomnia. Her QTcF interval and LFTs remained within normal limits. She underwent a brain MRI due to worsening headaches with aura, which was negative for metastatic disease. At the initiation of Cycle 2, however, she was noted to have significantly elevated liver enzymes (aspartate aminotransferase/alanine aminotransferase [AST/ALT] 187/326). Ribociclib was held, and repeat laboratory testing 1 week later demonstrated persistent elevations.  

Over the subsequent weeks, the patient developed progressive nausea, weakness, and flu-like symptoms, ultimately requiring hospital admission. At that time, her AST/ALT had risen to 628/1068, while bilirubin remained normal. A liver ultrasound revealed no acute abnormalities, although transaminases continued to increase. Letrozole was held.

Letrozole-induced liver injury is rare, with an estimated incidence of approximately 1%, and its underlying mechanism remains unclear.⁴ A comprehensive evaluation including cytomegalovirus, Epstein–Barr virus, antinuclear antibodies, respiratory viral panel, and hepatitis serologies was negative, supporting a diagnosis of grade III–IV transaminitis suspicious for a drug-induced reaction. Hepatology was consulted to guide further management. Despite discontinuation of both letrozole and ribociclib, her AST/ALT continued to rise, peaking at 890/1,392, with bilirubin remaining within normal limits. Liver enzymes gradually began to downtrend, but only mildly, and they fluctuated over several months.

She was started on a prednisone 1 mg/kg taper, resulting in slow biochemical improvement. Liver biopsy demonstrated features consistent with resolving drug-induced liver injury, including mild portal fibrosis (trichrome/reticulin), with no abnormal iron deposition or evidence of alpha-1-antitrypsin deficiency. After completing the steroid taper, her liver enzymes rebounded, necessitating resumption of prednisone at 5 mg daily. Hepatology recommended transitioning from prednisone to mycophenolate mofetil because of the patient’s significant anxiety and panic symptoms associated with corticosteroid use; however, the patient declined because of concern for additional adverse events. She also obtained a second opinion at another academic center, which agreed with the proposed management plan.  

After approximately 3 months, the patient’s AST and ALT returned to normal. She continued surveillance with ctDNA but declined further AI therapy. She agreed to resume goserelin, which she continues to receive, but she has not restarted other endocrine therapy despite her prior positive MRD result. She remains under close monitoring with breast examinations, ctDNA testing, and laboratory evaluation every 3 months. Additionally, she is followed by a psychiatrist for management of persistent anxiety and panic symptoms experienced during adjuvant treatment.  

Discussion   

This case highlights the real-world challenges patients may face not only with adjuvant endocrine therapy but also with other oncologic therapies. It underscores the need for advanced practitioners (APs) to recognize the critical role endocrine therapy plays in reducing the risk of recurrence and metastasis among individuals with HR+ breast cancer. A Danish study of more than 4,500 premenopausal patients with breast cancer registered in the Danish Breast Cancer Group clinical database found that 1,001 women (22%) discontinued endocrine therapy. Notably, recurrence occurred in more than 20% of those who discontinued treatment compared with 11% among patients who completed the recommended therapy.⁵  

Adherence to clinical guidelines for adjuvant endocrine therapy in premenopausal women is essential. According to the National Comprehensive Cancer Network (NCCN), premenopausal patients at diagnosis should receive tamoxifen, with or without ovarian suppression; alternatively, an AI may be used with ovarian suppression.⁶ Interpreting menopausal status during and after chemotherapy can be challenging because amenorrhea is common and does not reliably indicate permanent ovarian failure. Although the NCCN defines menopause as the cessation of menses for at least 12 months, clinicians must recognize that amenorrhea in a previously premenopausal patient is not equivalent to ovarian suppression. For this reason, follicle-stimulating hormone (FSH) and estradiol levels may be used to help guide treatment decisions, although they are not definitive, and serial testing may be needed. Once tamoxifen is initiated, FSH levels become less reliable, making collaboration between oncology and gynecology particularly important.  

The benefits of ovarian suppression have been examined extensively. The SOFT trial, published in The New England Journal of Medicine in 2015, randomly selected 3,066 premenopausal women—stratified by chemotherapy use—to receive 5 years of tamoxifen alone, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. Although ovarian suppression did not significantly improve outcomes in the overall study population, it did reduce the risk of recurrence in higher-risk women who required chemotherapy. In this subgroup, ovarian suppression combined with an AI provided even greater risk reduction compared with tamoxifen-based therapy.⁷

The patient in this case fits into this higher-risk category, having been premenopausal at diagnosis with a T2, grade 3, PR-negative tumor and an elevated Oncotype score. Given these features, ovarian suppression with goserelin was indicated. Because she completed chemotherapy in 2021, she was not eligible for a CDK4/6 inhibitor at that time, and tamoxifen was initiated. 

However, the patient was unable to tolerate ovarian suppression with tamoxifen and subsequently discontinued endocrine therapy. ctDNA testing was obtained at baseline and monitored over time. ctDNA assays such as Signatera and Guardant Reveal have been studied across multiple cancers as tools for detecting MRD. In breast cancer, Signatera is FDA approved as a tumor-informed assay capable of detecting molecular residual disease after definitive therapy for early-stage disease. Shaw et al. reported a sensitivity of 88% and specificity of 95%, with a median lead time of more than 10 months before clinical relapse when testing high-risk patients every 6 months.⁸ Although ctDNA testing is covered by Medicare, its routine use is not currently incorporated into expert guidelines.  

NCCN guidelines now recommend considering adjuvant treatment with a CDK4/6 inhibitor in appropriate patients.⁶ The NATALEE trial, published in JAMA Oncology in 2025, reported that at 44 months, ribociclib plus a nonsteroidal AI (NSAI) demonstrated improved invasive disease–free survival compared with an NSAI alone, with consistent benefits across subgroups.² Given her risk profile, the patient in this case was an excellent candidate for the addition of a CDK4/6 inhibitor.  

Unfortunately, this patient developed grade III–IV transaminitis while receiving ribociclib, with biopsy confirming drug-induced hepatic toxicity. According to Common Terminology Criteria for Adverse Events version 5.0, grade III elevations in AST and ALT are defined as > 5-20 times the upper limit of normal when baseline values are normal, or > 5-20 times baseline when baseline values are abnormal.^9,10 Although hepatotoxicity is an uncommon side effect of ribociclib, the drug’s prescribing information reports grade 3-4 ALT elevations in 8% of patients and AST elevations in 4.7%, with grade 4 elevations occurring in 1.5% and 0.8%, respectively.¹¹  

The AP’s Role  

Endocrine therapy remains the cornerstone in the management of HR+ HER2- breast cancer, significantly reducing the risk of recurrence and improving long-term survival. Despite its proven benefit, adherence to endocrine therapy is often challenged by treatment-related side effects, leading many patients to discontinue therapy prematurely. This case highlights the role of the AP in addressing such barriers early on with frequent toxicity checks, providing supportive care options, and supporting patient decision-making to optimize adherence through patient-centered care.   

In this case, the patient experienced substantial difficulties tolerating endocrine therapy, reporting symptoms that affected daily function and overall quality of life. The AP’s involvement was central to navigating the area of distress. In everyday practice, the AP should be able to identify the specific adverse effects driving non-adherence and adjust symptom-management strategies. It is important to acknowledge the patient’s concerns regarding poor treatment tolerance and to reinforce that their experience is heard and validated. Strategies to move forward include implementing evidence-based interventions, evaluating alternative endocrine agents, and coordinating supportive services to offset side effects.   

As treatment resumed with endocrine therapy and a CDK4/6 inhibitor, the AP’s role continued to evolve, focusing on ongoing assessment and comprehensive management throughout the course of therapy. This included coordinating baseline and interval monitoring required for endocrine therapy, ovarian suppression with goserelin, and ribociclib. The AP ensured timely completion and interpretation of serial laboratory studies, including complete blood counts, liver function tests, and serum electrolytes, and supervised adherence to ECG surveillance for QTc monitoring.

Because the patient developed significant hepatotoxicity, the AP intensified monitoring, reviewed trends in transaminase elevations, and promptly communicated critical laboratory abnormalities to the oncology team. The AP also conducted focused clinical assessments for symptoms of hepatic dysfunction, such as right upper quadrant discomfort, jaundice, fatigue, or nausea, and provided patient education regarding warning signs that warranted urgent evaluation. Additionally, the AP coordinated dose interruptions and adjustments according to toxicity-management guidelines, reinforced medication adherence, and offered supportive care strategies to optimize treatment tolerance. Through this close surveillance and patient-centered communication, the AP helped facilitate early recognition and management of hepatotoxicity while maintaining treatment continuity and safety.  

Through it all, the AP consistently recognized the patient’s heightened treatment sensitivities and maintained a supportive, empathetic presence to promote comfort and trust.  

Conclusion   

This case illustrates the challenges many patients may encounter during adjuvant breast cancer treatment. Clinical decision-making in this setting is highly complex, often incorporating cancer staging and pathology, clinical trial data, biomarkers, genetic results, molecular profiling, and the patient’s overall medical history. Despite the strength of evidence-based guidelines, one cannot fully anticipate the individualized obstacles that may arise during a patient’s treatment course.  

Patients today are increasingly well informed about potential side effects and the data underlying their therapeutic options. As a result, they may develop personal preferences or make decisions that differ from the clinician’s recommended plan. APs are particularly well suited to care for patients undergoing adjuvant therapy because of their specialized knowledge and clinical expertise. In addition, APs play a vital role in patient education and in addressing psychosocial needs, offering critical support as patients manage the toxicities and emotional burdens associated with treatment.  

 References  

1. National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer Subtypes. Updated 2025. Accessed November 24, 2025. https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
2. 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;15:17588359231178125. doi:10.1177/17588359231178125.
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;11(11):1364-1372. doi:10.1001/jamaoncol.2025.3700.
4. National Institute of Diabetes and Digestive and Kidney Diseases. Letrozole. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Library of Medicine. Updated July 25, 2017. Accessed November 11, 2025. https://www.ncbi.nlm.nih.gov/books/NBK548381/
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6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Breast cancer (Version 5.2025). Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.
7. Francis PA; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436-446. doi:10.1056/NEJMoa1412379
8. Shaw JA, Page K, Wren E, et al. Serial postoperative ctDNA monitoring of breast cancer recurrence. JCO Precis Oncol. 2024;8:e2300456.
9. National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (5 × 7) [PDF]. Published November 27, 2017. Accessed November 11, 2025. https://dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events/ctcae-v5-5x7.pdf.
10. Foldi J, Rivero-Hinojosa S, Satta S, et al. Serial circulating tumor DNA (ctDNA) monitoring in early-stage, HR+/HER2-, invasive lobular carcinoma (ILC) of the breast and impact on clinical outcomes. J Clin Oncol. 2025;43(16_suppl):581.
11. Novartis Pharmaceuticals Corporation. Invasive disease-free survival in early breast cancer: Kisqali (ribociclib). Accessed November 11, 2025. https://www.kisqali-hcp.com/early-breast-cancer/efficacy/invasive-disease-free-survival.