What management approach is recommended for a patient with a history of hormone receptor-positive breast cancer, current recurrence in the supraclavicular lymph node, and a CHEK2 mutation?

Management of CHEK2 Mutation Carrier with Hormone Receptor-Positive Breast Cancer and Supraclavicular Recurrence

For this patient with hormone receptor-positive breast cancer recurring in the supraclavicular lymph node after CDK4/6 inhibitor therapy, chemotherapy combined with definitive locoregional radiotherapy is the recommended treatment, as the CHEK2 mutation does not alter standard oncologic management for established breast cancer. 1

Primary Treatment Approach

The presence of a CHEK2 mutation does not change treatment decisions for patients who have already developed breast cancer. 2 The supraclavicular recurrence after progression on CDK4/6 inhibitor and endocrine therapy represents endocrine-resistant disease requiring a fundamental change in therapeutic strategy. 1

Systemic Therapy Selection

• Chemotherapy is the appropriate systemic treatment given clear evidence of endocrine resistance after CDK4/6 inhibitor failure. 1, 2
• Taxane-based regimens should be prioritized, specifically weekly paclitaxel or docetaxel every 3 weeks as monotherapy if no prior taxane exposure in the adjuvant setting. 1
• For more aggressive disease control, docetaxel plus capecitabine can be considered. 1
• Sequential endocrine therapy should be avoided in this setting, as continuing hormone therapy delays effective treatment and allows disease progression. 1, 2

Locoregional Management

• Definitive radiotherapy to the supraclavicular region must be delivered in combination with systemic chemotherapy. 1
• Chemotherapy alone is insufficient for durable locoregional control of supraclavicular disease. 1
• This approach treats the recurrence with curative intent rather than purely palliative management. 1

Required Diagnostic Workup

Before initiating treatment, complete restaging is essential:

• 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, bone scan or PET-CT to confirm isolated locoregional recurrence versus distant metastases. 1
• Complete blood count, liver function tests, renal function, alkaline phosphatase, and calcium. 1, 2

CHEK2-Specific Considerations

The CHEK2 mutation has important implications for cancer predisposition but does not influence treatment decisions for established breast cancer:

• No specific targeted medical treatment is recommended for CHEK2 heterozygotes who develop cancer. 2
• CHEK2 is a moderate-penetrance gene with cancer risks influenced by family history and other modifiers, but this affects surveillance strategies for future cancers, not treatment of current disease. 2
• The mutation does not predict response to specific chemotherapy regimens or endocrine therapies. 2

Future Cancer Risk Management

While not affecting current treatment, the CHEK2 mutation warrants:

• Consideration of contralateral prophylactic mastectomy based on personalized risk estimates and shared decision-making, particularly given the high rate of bilateral tumors in CHEK2 carriers (up to 41%). 3, 2
• Family cascade testing, as 63-65% of CHEK2 mutation carriers have positive breast cancer family history. 3
• Colorectal and prostate cancer surveillance based on family history assessment. 2

Treatment Sequencing Algorithm

1. Complete restaging with imaging and biopsy confirmation with receptor retesting 1
2. Initiate systemic chemotherapy (taxane-based regimen) 1
3. Deliver definitive radiotherapy to supraclavicular region during or after chemotherapy 1
4. Consider maintenance endocrine therapy after chemotherapy completion if hormone receptors remain positive 1
5. Add bisphosphonates if bone metastases are identified 1, 4

Critical Pitfalls to Avoid

• Do not continue sequential endocrine therapy in the setting of clear endocrine resistance after CDK4/6 inhibitor progression. 1
• Do not treat supraclavicular recurrence as purely metastatic disease without attempting curative locoregional therapy with radiotherapy. 1
• Do not assume CHEK2 mutation status requires different chemotherapy selection or targeted therapy, as no CHEK2-specific treatments exist. 2
• Do not omit radiotherapy, as chemotherapy alone provides inadequate locoregional control. 1

If Distant Metastases Are Present

Should restaging reveal distant metastases beyond the supraclavicular region:

• Chemotherapy remains appropriate given endocrine resistance. 1, 4
• Palliative radiotherapy to the supraclavicular region should still be considered for symptom control or prevention of local complications. 1
• Treatment goals shift to quality of life and prolongation of survival rather than cure. 2, 4
• Bisphosphonates are effective for hypercalcemia and palliation of lytic bone metastases. 4, 2