What is the best course of treatment for a patient with a history of hormone receptor-positive breast cancer, who initially underwent lumpectomy, radiation, and oopherectomy, and was treated with Verzenio (abemaciclib) and letrozole for several years, now presenting with recurrence in the supraclavicular lymph node and enlarged lymph node?

Treatment Recommendation for Supraclavicular Lymph Node Recurrence After CDK4/6 Inhibitor and Endocrine Therapy

This patient with supraclavicular lymph node recurrence after progression on Verzenio (abemaciclib) and letrozole should receive chemotherapy as the primary systemic treatment, combined with definitive locoregional radiotherapy to the supraclavicular region, as this represents endocrine-resistant disease requiring a change in therapeutic approach. 1

Rationale for Chemotherapy Over Continued Endocrine Therapy

• Patients with evidence of endocrine resistance should be offered chemotherapy rather than sequential endocrine therapy 1
• This patient has demonstrated clear endocrine resistance, having progressed through multiple lines: letrozole, Verzenio (a CDK4/6 inhibitor) plus letrozole, and post-oophorectomy hormonal manipulation 1
• The supraclavicular recurrence represents locoregional progression that occurred despite aggressive endocrine-based therapy, indicating the tumor has developed mechanisms to bypass hormonal blockade 1

Specific Chemotherapy Regimen Selection

Recommended first-line chemotherapy options include: 1

• Taxane-based regimens (paclitaxel weekly or docetaxel every 3 weeks) as monotherapy, particularly if no prior taxane exposure in the adjuvant setting 1
• Docetaxel plus capecitabine if more aggressive disease control is needed 1
• Capecitabine monotherapy if patient has comorbidities or prefers oral therapy with better tolerability profile 1

The choice depends on prior adjuvant chemotherapy exposure, performance status, and patient preference for intravenous versus oral administration 1

Critical Role of Locoregional Radiotherapy

Definitive radiotherapy to the supraclavicular region (60 Gy in 30 fractions) must be incorporated into the treatment plan 2

• Supraclavicular lymph node recurrence without distant metastases should be treated with curative intent using combined chemotherapy and radical radiotherapy 2
• The radiation should be delivered as an "involved field" treatment, ideally between the third and fourth chemotherapy cycles 2
• This combined approach achieved 5-year overall survival of 35% and disease-free survival of 20% in patients with isolated supraclavicular recurrence 2
• The overall clinical response rate to combined chemotherapy and radiotherapy was 94.9% in this clinical scenario 2

Essential Diagnostic Workup Before Treatment

Complete restaging is mandatory to confirm this is truly locoregional recurrence without distant metastases: 1

• Biopsy confirmation of the supraclavicular lymph node with repeat ER/PR/HER2 testing, as receptor status can change at recurrence 1
• CT chest/abdomen/pelvis to identify visceral metastases 1
• Bone scan or PET-CT to exclude bone metastases 1
• Complete blood count, liver function tests, renal function, alkaline phosphatase, and calcium 1

If distant metastases are identified, this changes the treatment paradigm from curative to palliative intent, though chemotherapy would still be indicated 1

Why Not Continue Endocrine Therapy

Several factors argue strongly against sequential endocrine therapy:

• Progression on CDK4/6 inhibitor plus aromatase inhibitor represents high-grade endocrine resistance 1, 3
• The patient has exhausted multiple endocrine mechanisms: ovarian suppression (oophorectomy), aromatase inhibition (letrozole), and CDK4/6 inhibition (Verzenio) 1, 3
• While fulvestrant could theoretically be considered as it works through a different mechanism (selective estrogen receptor degrader), progression on CDK4/6 inhibitor therapy suggests aggressive biology requiring chemotherapy 1, 3
• Concomitant chemo-endocrine therapy is not recommended and offers no survival benefit 1

Treatment Sequencing Algorithm

Step 1: Complete restaging workup to confirm isolated locoregional recurrence 1

Step 2: If no distant metastases, initiate systemic chemotherapy (taxane-based preferred) 1, 2

Step 3: Deliver definitive radiotherapy (60 Gy) to supraclavicular region between chemotherapy cycles 3-4 2

Step 4: Complete 6 cycles of chemotherapy 2

Step 5: Consider maintenance endocrine therapy after chemotherapy completion, potentially with fulvestrant as this mechanism has not been exhausted 1, 3

Common Pitfalls to Avoid

• Do not continue sequential endocrine therapy in clear endocrine-resistant disease – this delays effective treatment and allows disease progression 1
• Do not treat supraclavicular recurrence as metastatic disease without attempting curative locoregional therapy – outcomes are significantly better than historically assumed when aggressive combined modality treatment is used 2
• Do not omit radiotherapy – chemotherapy alone is insufficient for durable locoregional control in this scenario 2
• Do not assume receptor status remains unchanged – repeat biopsy is essential as discordance occurs in 20-30% of recurrences 1

If Distant Metastases Are Present

If restaging reveals distant metastases (making this stage IV disease rather than isolated locoregional recurrence):

• Chemotherapy remains the appropriate choice given endocrine resistance 1, 4
• Palliative radiotherapy to the supraclavicular region can still be considered for symptom control or prevention of local complications 1
• Treatment duration should continue until disease progression or unacceptable toxicity rather than a fixed number of cycles 1, 3
• Bisphosphonates should be added if bone metastases are present 1