This review examines how immunotherapy, especially checkpoint inhibitors, is transforming breast cancer treatment. Key findings show that adding pembrolizumab to chemotherapy significantly improves outcomes for triple-negative breast cancer (TNBC) patients—boosting pathological complete response rates from 51% to 65% in early-stage cases and extending survival in advanced PD-L1-positive cases (23 vs. 16 months overall survival). For hormone receptor-positive (HR+) breast cancer, immunotherapy combinations increased response rates but with variable benefits. Biomarkers like PD-L1 status are critical for predicting treatment success, though research continues to refine patient selection.

Immunotherapy for Breast Cancer: Current Treatments and Future Directions

Table of Contents

• Introduction
• How Immunotherapy Works
• Current Landscape of Immunotherapy
• Triple-Negative Breast Cancer (TNBC): An Overview
• Immunotherapy in Early-Stage TNBC
• Immunotherapy After Surgery and Chemotherapy
• Immunotherapy for Advanced TNBC
• Immunotherapy in HR-Positive, HER2-Negative Breast Cancer
• Study Methods: How the Research Was Conducted
• Key Findings: Summary of Results
• Clinical Implications: What This Means for Patients
• Limitations of the Research
• Recommendations for Patients

Introduction

Breast cancer remains one of the most common cancers globally and the second leading cause of cancer deaths in the U.S. Despite treatment advances, recurrence and variable responses persist. Breast cancer is categorized into subtypes: hormone receptor-positive (HR+), HER2-positive, and triple-negative breast cancer (TNBC), which lacks estrogen, progesterone, and HER2 receptors. TNBC is particularly aggressive, accounting for 15-20% of cases, with poorer survival rates (64% 5-year survival for stages I-III). Traditionally considered "immunologically cold" (less responsive to immune treatments), recent clinical trials show immunotherapy—especially immune checkpoint inhibitors (ICIs)—can significantly help certain patients. Pembrolizumab is now FDA-approved for TNBC in both early and advanced stages when combined with chemotherapy. This review explores how immunotherapy works, which patients benefit most, and the role of biomarkers like PD-L1 in guiding treatment.

How Immunotherapy Works

Immunotherapy helps your immune system recognize and destroy cancer cells. The main types used in breast cancer are checkpoint inhibitors (like PD-1/PD-L1 inhibitors) and HER2-targeted antibodies. Cancer cells often evade detection by exploiting "checkpoint" proteins (PD-1/PD-L1), which act as "brakes" on immune cells. When PD-L1 on cancer cells binds to PD-1 on T-cells (a type of immune cell), it deactivates them. Checkpoint inhibitors block this binding, "releasing the brakes" so T-cells can attack tumors. For example, pembrolizumab blocks PD-1, while atezolizumab blocks PD-L1. Combining immunotherapy with chemotherapy enhances this effect: chemo kills cancer cells, releasing tumor proteins that alert the immune system, while immunotherapy activates T-cells to target remaining cancer cells. However, this immune activation can cause side effects like autoimmune reactions (e.g., thyroid issues or rashes), occurring in 7-23% of patients in trials.

Current Landscape of Immunotherapy

Three categories of checkpoint inhibitors exist: PD-1 inhibitors (pembrolizumab, nivolumab), PD-L1 inhibitors (atezolizumab, durvalumab), and CTLA-4 inhibitors (ipilimumab). Only pembrolizumab is currently FDA-approved for breast cancer (specifically TNBC) after atezolizumab was withdrawn due to trial results. Not all patients respond equally—about 40-60% of TNBC patients benefit, depending on biomarkers. Research focuses on improving patient selection and expanding immunotherapy use to other subtypes.

Triple-Negative Breast Cancer (TNBC): An Overview

TNBC is aggressive, with limited treatment options since it doesn't respond to hormone therapies. It represents 15-20% of breast cancers and has higher recurrence rates (30-35% within 3 years for stage II/III). Immunotherapy works better in TNBC than other subtypes due to its higher tumor mutational burden (TMB)—more genetic mutations make tumors more visible to the immune system. Pembrolizumab combined with chemo is now standard for early-stage high-risk TNBC and advanced PD-L1-positive TNBC. Key trials show immunotherapy is most effective early in the disease, before the immune system is weakened by cancer progression or prior treatments.

Immunotherapy in Early-Stage TNBC

For early-stage TNBC (stages II-III), adding pembrolizumab to chemotherapy before surgery (neoadjuvant therapy) significantly improves outcomes. In the KEYNOTE-522 trial (1,174 patients), those receiving pembrolizumab + chemo had a 65% pathological complete response (pCR) rate—meaning no detectable cancer after treatment—versus 51% with chemo alone. After 5 years, 81.3% of pembrolizumab patients were cancer-free versus 72.3% without it, reducing recurrence risk by 37%. Similar benefits appeared in other trials:

• IMpassion031 (333 patients): Atezolizumab + chemo increased pCR to 58% vs. 41%.
• I-SPY2 (114 patients): Pembrolizumab + chemo achieved 60% pCR vs. 20%.

Higher pCR correlates with better long-term survival. A meta-analysis of 1,496 TNBC patients confirmed immunotherapy boosts pCR rates. However, immune-related side effects occurred in 9-82% of patients (grade ≥3 in 7-23%).

Immunotherapy After Surgery and Chemotherapy

Patients with residual cancer after neoadjuvant chemo face high recurrence risk (57% 5-year survival vs. 90% with pCR). Immunotherapy after surgery (adjuvant therapy) aims to eliminate remaining cancer cells. In KEYNOTE-522, adjuvant pembrolizumab improved survival, especially in patients with moderate residual disease. However, the ALEXANDRA trial (atezolizumab after chemo) showed no benefit—12.8% recurrence with immunotherapy vs. 11.4% without. This suggests pembrolizumab is effective post-surgery only in specific scenarios, highlighting the need for personalized approaches.

Immunotherapy for Advanced TNBC

For metastatic TNBC (mTNBC), immunotherapy extends survival in PD-L1-positive patients. Key trials include:

• KEYNOTE-355 (847 patients): Pembrolizumab + chemo improved median survival to 23 months vs. 16 months in PD-L1-positive patients (CPS ≥10). Progression-free survival (time without cancer worsening) increased to 9.7 months vs. 5.6 months.
• IMpassion130 (943 patients): Atezolizumab + chemo extended progression-free survival to 7.5 months vs. 5.3 months in PD-L1-positive patients. Overall survival trended higher (25.4 vs. 17.9 months) but wasn't statistically significant.

Conversely, IMpassion131 (902 patients) showed no benefit with atezolizumab + paclitaxel. Response depends heavily on PD-L1 status—only 40-50% of advanced TNBC patients are PD-L1-positive. Side effects (grade ≥3) occurred in 5-7.5% of patients.

Immunotherapy in HR-Positive, HER2-Negative Breast Cancer

HR+/HER2- breast cancer (65% of cases) is typically less responsive to immunotherapy due to lower immune cell infiltration. However, high-risk subtypes (e.g., high Ki-67 index) may benefit. Recent trials show:

• KEYNOTE-756 (1,278 patients): Adding pembrolizumab to neoadjuvant chemo increased pCR rates to 24.3% vs. 15.6%. Benefits were strongest in patients with low estrogen receptor expression (ER 1-9%), where pCR jumped to 59% vs. 30.2%.
• CheckMate 7FL (521 patients): Nivolumab + chemo improved pCR to 24.5% vs. 13.8%, especially in PD-L1-positive patients (44.3% vs. 20.2%).

Grade 3-4 side effects occurred in 32-52.5% of patients. While promising, immunotherapy isn't yet standard for HR+ breast cancer outside clinical trials.

Study Methods: How the Research Was Conducted

This review analyzed data from major phase II/III clinical trials published through 2024. Trials like KEYNOTE-522 (early TNBC), KEYNOTE-355 (advanced TNBC), and KEYNOTE-756 (HR+ breast cancer) compared immunotherapy-drug combinations against placebos or standard chemo. Studies included 300-1,200+ patients, tracked outcomes like pCR (pathological complete response), overall survival (OS), progression-free survival (PFS), and side effects. Biomarkers (PD-L1, TMB) were assessed using tumor tissue tests. Results were statistically validated—e.g., hazard ratios (HR) below 1.0 indicate treatment benefit, with p-values <0.05 confirming significance.

Key Findings: Summary of Results

• Early TNBC: Pembrolizumab + chemo boosts pCR rates by 14-40% (65% vs. 51% in KEYNOTE-522) and 5-year cancer-free survival by 9% (81.3% vs. 72.3%).
• Advanced TNBC: Pembrolizumab + chemo extends survival by 7 months (23 vs. 16 months) in PD-L1-positive patients.
• HR+ Breast Cancer: Immunotherapy increases pCR by 8.5-10.7% but benefits are limited to high-risk subgroups.
• Biomarkers Matter: PD-L1-positive patients (using CPS ≥10 or tumor-infiltrating lymphocytes) respond best. TNBC patients with high tumor mutation burden also show improved responses.
• Safety: Grade ≥3 immune-related side effects occurred in 5-23% of patients across trials.

Clinical Implications: What This Means for Patients

For TNBC patients, pembrolizumab combined with chemotherapy is now a standard option. Early-stage patients with high-risk tumors (stage II/III) should discuss neoadjuvant pembrolizumab + chemo, which reduces recurrence risk by 37%. Advanced TNBC patients with PD-L1-positive tumors (about 40-50%) may live longer with first-line pembrolizumab + chemo. For HR+ patients, immunotherapy is emerging for high-risk cases with low hormone receptor levels or aggressive features—though it's not yet routine. All patients should be tested for PD-L1 (via biopsy) to determine eligibility. Those starting immunotherapy need monitoring for autoimmune side effects like fatigue, rash, or thyroid issues.

Limitations of the Research

Key unanswered questions remain: Immunotherapy doesn't help PD-L1-negative TNBC patients, and biomarkers beyond PD-L1 (like tumor mutation burden) need validation. Benefits in HR+ breast cancer are modest and restricted to subgroups. Early recurrence after chemo-immunotherapy (within 6 months) wasn't studied, and long-term survival data for newer combinations is limited. Adjuvant immunotherapy after surgery shows inconsistent results—effective in some trials (KEYNOTE-522) but not others (ALEXANDRA). Finally, side effects like adrenal insufficiency (seen in I-SPY2) require careful management.

Recommendations for Patients

1. Discuss Biomarker Testing: Request PD-L1 testing (CPS score) if you have TNBC or high-risk HR+ breast cancer.
2. Consider Immunotherapy for TNBC: If eligible, pembrolizumab + chemo offers the strongest survival benefit for early-stage or PD-L1-positive advanced TNBC.
3. Ask About Clinical Trials: Explore trials for PD-L1-negative TNBC or HR+ disease—new combinations (e.g., immunotherapy + targeted drugs) are being studied.
4. Monitor Side Effects: Report symptoms like persistent fatigue, cough, or rash promptly during treatment.
5. Personalize Post-Surgery Care: If residual cancer remains after neoadjuvant therapy, discuss pembrolizumab with your oncologist.