What are the response rates to immunotherapy in a patient with metastatic breast cancer and liver and ovarian involvement who tests positive for PD-L1 (Programmed Death-Ligand 1) or MMR/MSI-H (Mismatch Repair/Microsatellite Instability-High)?

Response Rates to Immunotherapy in PD-L1-Positive or MSI-H Metastatic Breast Cancer

For metastatic triple-negative breast cancer (TNBC) with PD-L1 positivity, immunotherapy combined with chemotherapy achieves response rates of approximately 40-46% in first-line treatment, with pembrolizumab plus chemotherapy improving progression-free survival from 5.6 to 9.7 months (HR 0.65) in patients with CPS ≥10, and atezolizumab plus nab-paclitaxel improving overall survival from 15.1 to 25 months in PD-L1-positive disease. 1, 2

Response Rates Based on Biomarker Status

PD-L1-Positive Metastatic TNBC

• Pembrolizumab plus chemotherapy achieves a progression-free survival improvement from 5.6 to 9.7 months (HR 0.65, P=0.0012) specifically in patients with Combined Positive Score (CPS) ≥10 using the 22C3 assay 1, 2

• Atezolizumab plus nab-paclitaxel demonstrates response rates with 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—representing a clinically meaningful 7-month survival benefit 1, 2

• Single-agent PD-1/PD-L1 inhibitors in heavily pretreated metastatic TNBC show response rates of 4.8-19% in PD-L1-positive disease, with higher responses in triple-negative compared to hormone receptor-positive disease 3, 4

• Combination immunotherapy with nab-paclitaxel in first-line metastatic TNBC achieved 38-46% confirmed response rates in phase Ib trials, even in PD-L1-unselected populations 4, 5

MSI-H Status in Breast Cancer

• MSI-H breast cancers are extremely rare (approximately 1.1% prevalence), making response rate data specific to this biomarker in breast cancer limited 6

• The ESMO guidelines note that 75% of breast cancers with high tumor mutational burden and/or MSI are PD-L1 positive, suggesting potential immunotherapy responsiveness, though MSI-high with low TMB is rare except in endometrial cancer 6

• MSI, TMB, and PD-L1 expression are recognized markers for immunotherapy selection, but their prevalence and predictive role differ substantially by tumor type 6

Critical Treatment Selection Algorithm

Step 1: Confirm Eligibility Criteria

• Verify triple-negative status (hormone receptor-negative, HER2-negative) with liver and ovarian metastases 1

• Confirm timing requirement: Immunotherapy is only indicated if metastatic disease developed de novo OR at least 12 months after completion of (neo)adjuvant chemotherapy 1, 2

• Obtain mandatory PD-L1 testing using the FDA-approved companion diagnostic specific to the intended agent before initiating therapy 1, 2

Step 2: Select Appropriate PD-L1 Assay

• For pembrolizumab: Use 22C3 assay requiring CPS ≥10 (evaluates tumor cells, lymphocytes, and macrophages) 1, 2

• For atezolizumab: Use SP142 assay requiring ≥1% PD-L1 expression on immune cells (evaluates immune cells in tumor and stroma) 1, 2

• These assays are NOT interchangeable—the specific assay validated in the supporting clinical trial must be used 1, 2

Step 3: Choose First-Line Regimen Based on PD-L1 Result

• If PD-L1 CPS ≥10 (22C3 assay): Pembrolizumab plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) 1

• If PD-L1 ≥1% on immune cells (SP142 assay): Atezolizumab plus nab-paclitaxel specifically (NOT standard paclitaxel, as IMpassion131 showed no PFS benefit with paclitaxel: 6.0 vs 5.7 months, HR 0.82, P=0.20) 1, 2

• If PD-L1 negative: Immunotherapy should NOT be used; proceed with chemotherapy alone 1

MSI-H Specific Considerations

• For the rare MSI-H breast cancer: While pembrolizumab has tissue-agnostic FDA approval for MSI-H/dMMR solid tumors, specific response rate data in breast cancer is lacking due to extreme rarity 6

• Confirm MSI-H status using both MMR-IHC (all four proteins: MLH1, MSH2, MSH6, PMS2) AND MSI-PCR (five poly-A panel: BAT-25, BAT-26, NR-21, NR-24, NR-27) to avoid false positives that occurred in approximately 10% of metastatic colorectal cancer patients 6

• NGS-based MSI testing represents an alternative that can simultaneously assess TMB and identify other targetable alterations (BRCA1/2 mutations relevant for ovarian involvement) 6

Common Pitfalls to Avoid

• Do NOT use immunotherapy monotherapy in later lines—response rates are too low; immunotherapy must be combined with chemotherapy in the first-line setting 1

• Do NOT initiate immunotherapy if disease recurred within 12 months of completing (neo)adjuvant chemotherapy—this is an exclusion criterion for benefit 1, 2

• Do NOT assume PD-L1 assays are interchangeable—using the wrong assay will lead to inappropriate patient selection and treatment failure 1, 2

• Do NOT reserve carboplatin only for BRCA-mutated patients—carboplatin is appropriate for all TNBC patients regardless of BRCA status, particularly after prior anthracycline exposure 1

• Do NOT overlook immune-related adverse events—grade 3-4 events occur in 5% of pembrolizumab-treated patients, with treatment-related deaths in 0.7% of atezolizumab and 0.2% of pembrolizumab patients 2

Limitations of Current Evidence

• Approximately 40% of PD-L1-positive TNBC patients do not respond to immunotherapy plus chemotherapy, indicating that PD-L1 alone is insufficient as a predictive biomarker 7

• Response rates vary significantly based on tumor immunogenicity, with inflamed tumors responding better than immune-desert tumors 8

• Additional biomarkers beyond PD-L1 (tumor-infiltrating lymphocytes, CD8 T cell levels, IFNγ signatures) may be needed for more precise patient selection 8, 7