What is the role of immunotherapy in the treatment of breast cancer?

Immunotherapy in Breast Cancer

Immunotherapy is currently indicated only for triple-negative breast cancer (TNBC), where it has demonstrated survival benefits in both early-stage and metastatic settings when combined with chemotherapy. 1

Triple-Negative Breast Cancer (TNBC)

Early-Stage TNBC (Stage I-III)

For high-risk early-stage TNBC, pembrolizumab combined with neoadjuvant chemotherapy is the standard of care, regardless of PD-L1 status. 2

• The preferred neoadjuvant regimen consists of chemotherapy (taxanes, carboplatin, anthracyclines, and cyclophosphamide) combined with concurrent pembrolizumab 2
• The benefit from pembrolizumab is independent of PD-L1 expression in the neoadjuvant setting 2
• Adjuvant pembrolizumab should be continued after neoadjuvant therapy regardless of pathologic response 2
• For stage I TNBC with higher-risk features, consider adding carboplatin and pembrolizumab to the treatment regimen 2

Metastatic TNBC

For first-line treatment of metastatic TNBC, immunotherapy plus chemotherapy is recommended based on PD-L1 status:

PD-L1-Positive Disease (≥1% immune cells)

• Atezolizumab plus nab-paclitaxel is an approved option for first-line therapy in PD-L1-positive triple-negative advanced breast cancer, either de novo or at least 12 months after (neo)adjuvant chemotherapy 1

• The IMpassion-130 trial demonstrated progression-free survival improvement from 5.0 to 7.5 months (HR 0.62, P<0.001) and overall survival improvement from 15.1 to 25 months (7-month difference) in PD-L1-positive patients 1

• PD-L1 testing must use the SP142 immunohistochemical assay (Ventana Medical Systems) with ≥1% immune cell staining as the threshold 1

• Pembrolizumab plus chemotherapy is another first-line option for PD-L1-positive metastatic TNBC 1

• The KEYNOTE-355 trial showed progression-free survival improvement from 5.6 to 9.7 months (HR 0.65, P=0.0012) for PD-L1-positive disease (combined positive score ≥10) 1

• This regimen demonstrates superior overall survival benefit and is now considered standard of care 2, 3

PD-L1-Negative Disease

• Single-agent chemotherapy is preferred over combination chemotherapy for PD-L1-negative metastatic TNBC 2
• Immunotherapy is not recommended for PD-L1-negative disease in routine clinical practice 1

Later-Line Therapy

Checkpoint inhibitor monotherapy is NOT recommended in later lines for triple-negative breast cancer due to low response rates (Level I evidence, Grade E recommendation). 1

• The KEYNOTE-199 trial demonstrated insufficient efficacy for pembrolizumab monotherapy in pretreated TNBC 1
• For heavily pretreated patients (≥2 prior therapies), sacituzumab govitecan is strongly recommended over immunotherapy 2

Non-Triple-Negative Breast Cancer

Immunotherapy should NOT be used in routine clinical practice for any other biological subtype of breast cancer outside clinical trials (Level III evidence, Grade D recommendation, 85% consensus). 1

HER2-Positive Breast Cancer

• Pembrolizumab plus trastuzumab produced objective responses in PD-L1-positive tumors with advanced trastuzumab-resistant HER2-positive breast cancer 1
• Atezolizumab plus T-DM1 did not improve overall progression-free survival in the KATE2 trial, though subgroup analyses suggested benefit in PD-L1-expressing tumors 1
• Multiple ongoing trials are evaluating immunotherapy in HER2-positive early breast cancer (IMpassion050, APTneo, Keyriched-1, neoHIP, ASTEFANIA) 1
• Current recommendation: Use only in clinical trials 1

Hormone Receptor-Positive (HR+) Breast Cancer

• Several ongoing trials are evaluating immunotherapy in HR-positive subtypes 1
• Current recommendation: Not recommended outside clinical trials 1
• Breast cancer is not a highly immunogenic tumor overall, though TNBC shows greater immunogenicity 1

Critical Caveats and Common Pitfalls

PD-L1 Testing Requirements

• For metastatic TNBC, PD-L1 testing is mandatory before initiating immunotherapy 1
• Use only the validated companion diagnostic (SP142 assay for atezolizumab) 1
• Different assays and scoring systems exist for different checkpoint inhibitors (SP142 for atezolizumab vs. combined positive score for pembrolizumab) 1
• In the neoadjuvant setting for early-stage TNBC, PD-L1 testing is NOT required as benefit is independent of PD-L1 status 2

Timing Considerations

• For metastatic disease, immunotherapy is only indicated if disease developed de novo or at least 12 months after completion of (neo)adjuvant chemotherapy 1
• Do not use immunotherapy in patients who progressed within 12 months of adjuvant therapy 1

Sequencing with Other Therapies

• In patients with both PD-L1-positive disease and germline BRCA1/2 mutations, PARP inhibitors are the preferred treatment option over immunotherapy for metastatic TNBC 1, 2
• The optimal sequencing between immunotherapy and PARP inhibitors remains under investigation 1

Toxicity Monitoring

• Immune-related adverse events can be irreversible and life-threatening 4
• The lack of predictive accuracy of PD-L1 expression in early-stage settings raises concerns about exposing patients to toxicity without clear benefit markers 4