Key messages
• For people with early triple-negative breast cancer (TNBC) (that is potentially curable breast cancer, stages 1 to 3), adding PD-1 or PD-L1 inhibitors (immunotherapy) to chemotherapy before surgery improves the chances of having no signs of cancer at the time of surgery, the length of time lived without the cancer returning, and the length of time from diagnosis or treatment start until death from any cause compared to chemotherapy alone. However, the addition of immunotherapy likely increases the risk of serious unwanted effects. Quality of life and overall unwanted effects may be similar between the two treatments.
• There do not appear to be improvements in survival outcomes when immunotherapy is added to chemotherapy after surgery.
• Future studies should look at how PD-1 or PD-L1 inhibitors work in different groups and focus on outcomes such as quality of life during and after treatment.
What are PD-1 or PD-L1 inhibitors?
PD-1 and PD-L1 inhibitors are medicines used in cancer treatment as part of a type of therapy called immunotherapy. They work by helping the immune system respond more effectively to cancer. Some cancer cells can avoid being noticed by the immune system by using a signal involving two proteins called PD-1 and PD-L1. PD-1 and PD-L1 inhibitors block that signal, making it easier for the immune system to find and respond to cancer cells.
Why is this important for people with early triple-negative breast cancer (TNBC)?
TNBC is an aggressive type of breast cancer that makes up about 12% to 17% of breast cancer cases. It can be more difficult to treat than other types of breast cancer. Chemotherapy, given before or after surgery, is the standard treatment, and can help improve survival. However, around 30% to 40% of people with early TNBC will still develop cancer that spreads to other parts of the body (metastasis).
New treatments are being studied that combine chemotherapy with PD-1 or PD-L1 inhibitors, which help the immune system respond to cancer. Research indicates that this combination may improve treatment results. Understanding whether this combination is safe and effective is important so that doctors and patients can make informed decisions about care.
What did we want to find out?
We wanted to know if combining PD-1 or PD-L1 inhibitors with chemotherapy works better than chemotherapy alone for people with early TNBC and if it is safe.
What did we do?
We searched for studies that compared PD-1 or PD-L1 inhibitors combined with chemotherapy and chemotherapy alone. We reviewed and summarised the results and rated our confidence in the findings based on factors such as study methods and sizes.
What did we find?
We found seven studies with a total of 4341 people. Two studies used PD-1 inhibitors (i.e. pembrolizumab) and five used PD-L1 inhibitors (i.e. durvalumab, atezolizumab). Six studies gave treatment before surgery, and one study gave treatment after surgery.
In studies comparing PD-1 or PD-L1 inhibitors combined with chemotherapy to chemotherapy alone before surgery, people who received combined therapy:
• were more likely to have no signs of cancer at the time of surgery (about twice as many people had this result compared to those who received chemotherapy alone);
• lived longer without cancer coming back; and
• lived longer from the start of diagnosis or treatment until death from any cause.
There may be little or no difference between groups in quality of life. There is probably little or no difference between groups in overall unwanted effects or treatment-related deaths. Serious unwanted effects were more common and related to immunotherapy compared to chemotherapy alone.
In a single study comparing PD-1 or PD-L1 inhibitors combined with chemotherapy to chemotherapy alone after surgery, there did not appear to be improvements in survival outcomes in the combined therapy group.
What are the limitations of the evidence?
Whilst we are confident to moderately confident that adding PD-1 or PD-L1 inhibitors to chemotherapy before surgery improves survival outcomes, we have only moderate to little confidence in the results of using these medicines after surgery because the number of people in the one included study was too small to draw firm conclusions, and it is possible that people in the study knew which treatment they were getting.
How up-to-date is the evidence?
The evidence is current to 6 November 2024.
Read the full abstract
Triple-negative breast cancer (TNBC), an aggressive subtype lacking oestrogen and progesterone receptors and amplification of HER2 receptors, accounts for 12% to 17% of breast cancers. Adjuvant and neoadjuvant chemotherapy improve survival; however, 30% to 40% of early-stage TNBC cases progress to metastatic disease. Recent evidence suggests that combining immune checkpoint inhibitors (PD-1/PD-L1 inhibitors) with chemotherapy may improve pathological complete response and event-free survival.
Objectives
To assess the benefits and harms of immune checkpoint inhibitors (PD-1 or PD-L1 inhibitors) plus chemotherapy compared with chemotherapy for people with early TNBC.
Search strategy
We searched the Cochrane Breast Cancer Group Specialised Register, CENTRAL, MEDLINE, Embase, the WHO ICTRP, and ClinicalTrials.gov up to 6 November 2024. We also searched the reference lists of identified relevant trials or reviews for potentially eligible studies.
Selection criteria
Randomised controlled trials (RCTs) comparing PD-1 or PD-L1 inhibitors plus chemotherapy with chemotherapy alone in participants with early TNBC.
Data collection and analysis
Pairs of review authors independently identified studies for inclusion and performed data extraction and risk of bias assessment. Outcomes were pathological complete response, event-free survival (EFS), overall survival (OS), health-related quality of life (HRQoL), and overall rates of any adverse events and serious adverse events (SAEs). We calculated hazard ratios (HRs) for time-to-event data, risk ratios (RRs), odds ratios (ORs), or risk differences (RDs) for dichotomous outcomes, and mean differences (MDs) for continuous outcomes with corresponding 95% confidence intervals (CIs). We performed random-effects meta-analyses to summarise the evidence and evaluated the certainty of evidence using the GRADE approach.
Main results
We included seven RCTs with a total of 4341 participants. Two trials investigated PD-1 inhibitors (i.e. pembrolizumab), and five investigated PD-L1 inhibitors (i.e. durvalumab, atezolizumab) in the intervention group. Six studies used neoadjuvant chemotherapy (NACT), and one study used adjuvant chemotherapy (ACT) in the control group. The studies cover a five-year follow-up period. Two studies were at low risk of bias for all reported outcomes. The main limitation of the other trials was lack of blinding.
PD-1 or PD-L1 inhibitors plus chemotherapy versus chemotherapy alone before breast cancer surgery
PD-1 or PD-L1 inhibitors plus chemotherapy probably increase pathological complete response rate (RR 1.47, 95% CI 1.15 to 1.86; 6 studies, 1564 participants; moderate-certainty evidence); improve EFS (HR 0.64, 95% CI 0.52 to 0.79; 4 studies, 1789 participants; high-certainty evidence); and probably improve OS (HR 0.56, 95% CI 0.34 to 0.93; 3 studies, 1681 participants; moderate-certainty evidence) compared with chemotherapy alone. There may be little or no difference between PD-1 or PD-L1 inhibitors plus chemotherapy and chemotherapy alone in HRQoL (MD −1.49, 95% CI −3.88 to 0.91; 2 studies, 1395 participants; low-certainty evidence). PD-1 or PD-L1 inhibitors plus chemotherapy probably have little or no effect on any adverse events (OR 0.26, 95% CI 0.05 to 1.24; 3 studies, 1781 participants; moderate-certainty evidence) and treatment-related deaths (RD 0.2%, 95% CI −0.4% to 0.8%; 4 studies, 1761 participants; moderate-certainty evidence) compared with chemotherapy alone. PD-1 or PD-L1 inhibitors plus chemotherapy probably increase immune-related SAEs (OR 1.75, 95% CI 1.15 to 2.67; 5 studies, 2016 participants; moderate-certainty evidence) compared with chemotherapy alone.
PD-1 or PD-L1 inhibitors plus chemotherapy versus chemotherapy alone after breast cancer surgery
There may be little or no difference between PD-1 or PD-L1 inhibitors plus chemotherapy and chemotherapy alone in EFS (HR 1.11, 95% CI 0.87 to 1.42; 1 study, 2199 participants; low-certainty evidence), OS (HR 1.23, 95% CI 0.87 to 1.73; 1 study, 2199 participants; low-certainty evidence), HRQoL (MD −1.02, 95% CI −2.71 to 0.67; 1 study, 2168 participants; low-certainty evidence), any adverse events (OR 3.38, 95% CI 0.93 to 12.33; 1 study, 2177 participants; low-certainty evidence), and treatment-related deaths (RD −0.1%, 95% CI −0.4% to 0.2%; 1 study, 2177 participants; low-certainty evidence). PD-1 or PD-L1 inhibitors plus chemotherapy probably increase immune-related SAEs (OR 1.81, 95% CI 1.47 to 2.24; 1 study, 2177 participants; moderate-certainty evidence) compared to chemotherapy alone.
Authors' conclusions
Combining PD-1 or PD-L1 inhibitors with chemotherapy compared to chemotherapy alone before breast cancer surgery improves pathological response, EFS, and OS in early TNBC. In contrast, the combination of PD-1/PD-L1 inhibitors with chemotherapy after breast cancer surgery may have little to no effect on EFS and OS in early-stage TNBC when compared with chemotherapy alone. The addition of PD-1 or PD-L1 inhibitors probably increases immune-related SAEs.
