Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a promising treatment for certain breast cancer subtypes. Key trials show that adding drugs like pembrolizumab to chemotherapy significantly improves outcomes for triple-negative breast cancer (TNBC) patients—boosting pathological complete response rates by 14–38% in early-stage disease and extending survival in metastatic PD-L1-positive cases. For hormone receptor-positive (HR+), HER2-negative breast cancer, immunotherapy combinations doubled pCR rates in high-risk patients. However, benefits depend on biomarkers like PD-L1 expression, and immune-related side effects require careful management.

Immunotherapy in Breast Cancer: Current Treatments and Breakthroughs

Table of Contents

• Introduction: Why Immunotherapy Matters
• How Immunotherapy Works Against Cancer
• Immunotherapy in Triple-Negative Breast Cancer (TNBC)
• Immunotherapy in Hormone Receptor-Positive Breast Cancer
• What This Means for Patients
• Current Challenges and Limitations
• Patient Recommendations
• Source Information

Introduction: Why Immunotherapy Matters

Breast cancer remains the second leading cause of cancer death in the United States, despite advances in detection and treatment. Incidence rates are rising, especially in women under 50. Traditional therapies don't work equally well for all subtypes, which include:

• HR+/HER2- (hormone receptor-positive, HER2-negative): 65% of cases
• HER2-positive: Less common
• Triple-negative breast cancer (TNBC): Lacks estrogen, progesterone, and HER2 receptors

TNBC is particularly aggressive, with a 30–35% distant recurrence rate within 3 years for early-stage patients and only 64% 5-year survival. Immunotherapy—which harnesses the immune system to fight cancer—has revolutionized treatment for melanoma and lung cancer but arrived later for breast cancer. In 2021, pembrolizumab became the first FDA-approved immunotherapy for TNBC, used alongside chemotherapy. This review explains how these treatments work, which patients benefit most, and key clinical trial results shaping current care.

How Immunotherapy Works Against Cancer

Immunotherapy drugs called immune checkpoint inhibitors (ICIs) block proteins like PD-1 or PD-L1 that cancer cells use to "hide" from immune cells. Normally, when PD-L1 on cancer cells binds to PD-1 on T-cells (a type of immune cell), it sends an "off" signal. ICIs prevent this binding, allowing T-cells to recognize and destroy cancer cells.

Combining ICIs with chemotherapy boosts effectiveness. Chemotherapy kills cancer cells, releasing tumor proteins that alert the immune system. ICIs then activate T-cells to attack remaining cancer cells. However, this activation can cause immune-related adverse effects (irAEs), where the immune system attacks healthy tissues. These range from rashes to severe autoimmune conditions and occur in 7–82% of patients depending on the regimen.

Three main ICI types are used:

• PD-1 inhibitors: Nivolumab, pembrolizumab
• PD-L1 inhibitors: Atezolizumab, durvalumab
• CTLA-4 inhibitor: Ipilimumab

Immunotherapy in Triple-Negative Breast Cancer (TNBC)

TNBC lacks targets for hormone therapy, making chemotherapy the primary option until immunotherapy emerged. TNBC often responds to ICIs due to its high tumor mutation burden (TMB), which creates more targets for immune cells. Benefits are greatest when treatment starts early.

Early-Stage TNBC

For stage II-III TNBC, adding pembrolizumab to neoadjuvant (pre-surgery) chemotherapy is now standard. Key trials:

• KEYNOTE-522 (1,174 patients): Pembrolizumab + chemo increased pathological complete response (pCR) rates from 51% to 65%. After 5 years, event-free survival (no recurrence/progression) was 81.3% vs. 72.3% with chemo alone—a 37% risk reduction.
• IMpassion031 (333 patients): Atezolizumab + chemo improved pCR from 41% to 58%.
• I-SPY2 (114 patients): Pembrolizumab + chemo doubled pCR rates (60% vs. 20%).

Patients achieving pCR had the best long-term outcomes. Immune-related severe side effects occurred in 9–82% of patients across trials.

Post-Treatment and Advanced TNBC

For patients with residual disease after neoadjuvant therapy:

• Pembrolizumab shows benefit, especially in those with moderate residual cancer (84% 3-year survival vs. 30% in high-residual disease).
• Atezolizumab failed in the IMpassion030 trial: No survival improvement vs. chemo alone (12.8% vs. 11.4% disease-free survival).

For metastatic TNBC (847–943 patients across trials):

• KEYNOTE-355: Pembrolizumab + chemo improved survival in PD-L1-positive patients (CPS ≥10): Median overall survival (OS) 23.0 vs. 16.1 months; progression-free survival (PFS) 9.7 vs. 5.6 months.
• IMpassion130: Atezolizumab + chemo extended PFS (7.2 vs. 5.5 months) but not OS overall. PD-L1-positive subgroups saw OS gains (25.4 vs. 17.9 months).
• IMpassion131: Atezolizumab + paclitaxel showed no benefit (PFS 5.7 vs. 5.6 months).

PD-L1 status is critical: Only PD-L1-positive patients consistently benefit. Severe immune-related side effects occurred in 5.3–7.5% of patients.

Immunotherapy in Hormone Receptor-Positive Breast Cancer

HR+/HER2- breast cancer is less immunogenic but benefits high-risk patients (e.g., high Ki-67 proliferation index). Two major trials show promise:

• KEYNOTE-756 (1,278 patients): Pembrolizumab + neoadjuvant chemo doubled pCR rates (24.3% vs. 15.6%). Patients with low estrogen receptor (ER 1–9%) saw the largest gain (59% vs. 30.2%). Grade ≥3 side effects: 52.5% vs. 46.4%.
• CheckMate 7FL (521 patients): Nivolumab + chemo increased pCR from 13.8% to 24.5%. PD-L1-positive patients (CPS ≥1) benefited most (44.3% vs. 20.2%). Severe side effects: 35% vs. 32%.

These results suggest immunotherapy could become an option for aggressive HR+ disease, though more research is needed.

What This Means for Patients

Immunotherapy combinations are transforming care for specific breast cancer subtypes:

• Early-stage TNBC: Pembrolizumab with chemo before surgery reduces recurrence risk by 37% and is now standard for stage II-III.
• Metastatic TNBC: Pembrolizumab + chemo extends survival for PD-L1-positive patients by nearly 7 months.
• High-risk HR+ disease: Immunotherapy may double pCR rates when added to chemo.

Biomarkers like PD-L1 (tested via tumor biopsies) are essential for identifying likely responders. Patients with "immune-hot" tumors (high TILs, TMB, or PD-L1) benefit most.

Current Challenges and Limitations

Despite progress, key limitations exist:

• Biomarker dependence: Only PD-L1-positive TNBC patients consistently respond. Reliable biomarkers for HR+ disease are still being studied.
• Side effects: Immune-related adverse events (e.g., thyroid dysfunction, colitis) occur in up to 82% of patients and require steroids or treatment pauses.
• Unanswered questions: Benefits in PD-L1-negative TNBC, optimal post-surgery regimens, and therapy for early recurrences (<6 months after treatment) remain unclear.
• Trial inconsistencies: Atezolizumab succeeded with nab-paclitaxel (IMpassion130) but failed with paclitaxel (IMpassion131), highlighting protocol sensitivity.

Patient Recommendations

Based on current evidence:

1. Discuss biomarker testing: Request PD-L1 (CPS score), TILs, or TMB testing if diagnosed with TNBC or high-risk HR+ breast cancer.
2. For early-stage TNBC: Ask about pembrolizumab + chemo before surgery, especially for stage II-III.
3. For metastatic TNBC: If PD-L1-positive, pembrolizumab + chemo is a first-line option.
4. Monitor side effects: Report rashes, diarrhea, or shortness of breath immediately—early management prevents complications.
5. Consider clinical trials: New ICI combinations (e.g., with antibody-drug conjugates) are being studied for resistant cases.

Source Information

Original Article Title: Immunotherapy in Breast Cancer
Authors: Kathrin Dvir, Sara Giordano, Jose Pablo Leone
Publication: International Journal of Molecular Sciences (2024), Volume 25, Issue 14
DOI: 10.3390/ijms25147517

This patient-friendly article is based on peer-reviewed research. Always consult your healthcare team for personal medical advice.