What is the best treatment regimen for a 68-year-old female with double primary hormone receptor-positive, HER2-negative breast cancer and non-small cell lung cancer (NSCLC) without driver mutations?

Treatment Approach for Double Primary HR+/HER2- Breast Cancer and NSCLC Without Driver Mutations

For this 68-year-old patient with synchronous HR+/HER2- breast cancer and NSCLC without driver mutations, sequential treatment prioritizing the more immediately life-threatening malignancy is recommended, with platinum-based chemotherapy for NSCLC followed by endocrine therapy for breast cancer, avoiding concurrent systemic therapies.

Initial Treatment Prioritization

Assess Disease Burden and Symptoms

• Determine which malignancy poses the greater immediate threat to survival by evaluating extent of metastatic disease, performance status (PS), and symptom burden 1.
• For NSCLC staging, obtain CT chest/abdomen, PET-CT for mediastinal nodes and distant metastases, and brain MRI given high sensitivity for CNS involvement 1.
• For breast cancer staging, perform CT chest/abdomen and bone imaging; PET-CT offers highest sensitivity if available 1.
• If the patient has extensive symptomatic visceral involvement from either cancer or PS ≥2, this determines treatment urgency and sequencing 1.

Treatment Sequencing Strategy

• Chemotherapy and endocrine therapy should NOT be given concomitantly for breast cancer 1.
• For elderly patients (age 70-89) with NSCLC and PS 0-2 with adequate organ function, carboplatin-based chemotherapy shows survival advantage 1.
• The standard first-line chemotherapy for NSCLC is platinum-based doublet chemotherapy 1.

NSCLC Treatment (First Priority if Symptomatic or Advanced)

First-Line Systemic Therapy for NSCLC

• For non-squamous NSCLC without driver mutations and unknown/negative PD-L1 (<1%), offer pembrolizumab + carboplatin + pemetrexed 1.
• If PD-L1 testing shows TPS 1-49%, pembrolizumab + chemotherapy remains appropriate with HR 0.65 for overall survival 1.
• Pemetrexed is preferred over gemcitabine or docetaxel in non-squamous tumors and should be restricted to non-squamous NSCLC in any line 1.
• For elderly patients or those with contraindications to immunotherapy, carboplatin-based doublet chemotherapy is recommended 1.
• Administer 4 cycles of chemotherapy (maximum 6 cycles) while patient maintains good PS 1.

Special Considerations for Elderly NSCLC Patients

• Single-agent chemotherapy with gemcitabine, vinorelbine, or taxanes represents an option for PS 2 patients 1.
• Treatment decisions must account for comorbidities and patient preferences within multidisciplinary tumor board 1.

Breast Cancer Treatment (Sequential After NSCLC Control)

Endocrine Therapy as Primary Treatment

• For HR+/HER2- metastatic breast cancer, endocrine therapy is the treatment of first choice independent of metastatic site, unless rapid response is needed 1.
• Limited visceral metastases are NOT a contraindication for endocrine therapy 1.
• For postmenopausal women, aromatase inhibitors (letrozole 2.5mg daily or anastrozole 1mg daily) are preferred over tamoxifen based on superior efficacy 1, 2, 3.
• Given low toxicity of endocrine therapy, endocrine maintenance should be considered 1.

When to Consider Chemotherapy for Breast Cancer

• Chemotherapy for breast cancer should only be considered if there is extensive symptomatic visceral involvement requiring rapid response 1.
• Sequential use of single-agent chemotherapy provides equivalent overall survival to combination chemotherapy for most patients 1.
• If chemotherapy is needed, single-agent therapy is preferred in patients without directly life-threatening disease 1.

Integration Strategy and Key Pitfalls

Multidisciplinary Coordination

• Treatment decisions should be discussed within a multidisciplinary tumor board for both malignancies 1.
• Patients with advanced lung cancer should be referred to interdisciplinary palliative care teams early in the course of disease, alongside active treatment 1.

Critical Pitfalls to Avoid

• Do NOT give concurrent chemotherapy and endocrine therapy for breast cancer 1.
• Do NOT use bevacizumab if patient has ECOG PS >1, clinically significant cardiovascular disease, or medically uncontrolled hypertension 1.
• Do NOT use single-agent immune checkpoint inhibitors for any EGFR alterations regardless of PD-L1 expression 1.
• Avoid omitting smoking cessation counseling, as it improves outcomes in any stage of NSCLC 1.

Monitoring and Reassessment

• Monitor PS closely as it determines eligibility for continued systemic therapy 1.
• For NSCLC, courses should not be repeated until neutrophil count ≥1,500 cells/mm³ and platelet count ≥100,000 cells/mm³ 4.
• Reassess disease burden after 4 cycles of NSCLC chemotherapy to determine maintenance strategy 1.
• In patients with non-squamous histology and PS 0-1, continuing pemetrexed maintenance following cisplatin-pemetrexed is recommended 1.

Practical Treatment Algorithm

1. Confirm PS 0-2 and adequate organ function 1
2. Initiate carboplatin + pemetrexed + pembrolizumab for NSCLC (if PD-L1 testing available and no contraindications) 1
3. After 4-6 cycles and disease control, transition to pemetrexed maintenance if non-squamous and PS 0-1 1
4. Once NSCLC is controlled/stable, initiate aromatase inhibitor (letrozole 2.5mg daily) for breast cancer 1, 2, 3
5. Continue endocrine therapy indefinitely given low toxicity profile 1