# Immunotherapy for Triple-Negative Breast Cancer: What Patients Need to Know Immunotherapy has become a powerful new tool in the fight against triple-negative breast cancer (TNBC), one of the most aggressive forms of breast cancer. This patient-friendly guide explains how immune checkpoint inhibitors—drugs that help the body's own immune system attack cancer cells—are now changing treatment for both early-stage and advanced TNBC. Based on a comprehensive medical review by experts at Dana-Farber Cancer Institute and Harvard Medical School, this article explains the key clinical trials, the numbers behind them, and what they mean for patients facing this diagnosis. # Immunotherapy for Triple-Negative Breast Cancer: What Patients Need to Know ## Table of Contents - Key Points - Introduction: A New Era for TNBC Treatment - Understanding TNBC and the Immune System - Immunotherapy for Early-Stage TNBC: The Evidence - Which Chemotherapy Works Best With Immunotherapy? - Timing and Sequencing: Before or After Surgery? - Biomarkers in Early-Stage Disease: Who Benefits Most? - Immunotherapy for Advanced-Stage TNBC - Treatment Duration, Sequencing, and Later Lines of Therapy - Biomarker Testing Challenges in Advanced Disease - Clinical Implications: What This Means for Patients - Limitations: What the Research Cannot Yet Answer - Recommendations for Patients - Frequently Asked Questions - Source Information ## Key Points - Immunotherapy with pembrolizumab plus chemotherapy is a new standard for stage 2-3 early TNBC, improving pCR from 51.2% to 64.8% in KEYNOTE-522. - In metastatic TNBC, pembrolizumab added to first-line chemotherapy improves survival only when tumors are PD-L1 positive with CPS ≥10. - PD-L1 testing is imperfect; different assays give different results, and expression can change over time or across metastatic sites. - The ideal chemotherapy backbone, timing of immunotherapy, and need for adjuvant therapy after surgery remain uncertain; ongoing trials are investigating these questions. - Immunotherapy can cause immune-related side effects like lung, colon, liver, or thyroid inflammation; report symptoms early for proper management. ## Introduction: A New Era for TNBC Treatment The arrival of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment across many tumor types, producing remarkably durable responses in patients with late-stage cancers. However, early studies initially failed to show similar benefits in breast cancer. The immune environment of breast cancer is very different from so-called "hot" tumors such as lung cancer or melanoma, where immune escape plays a major role in tumor progression and where the tumor mutational burden (TMB)—the number of genetic mutations in a tumor—may be substantially different. Triple-negative breast cancer (TNBC) is defined by the absence of three actionable targets: estrogen receptors, progesterone receptors, and HER2 amplification. For years, chemotherapy was the only available treatment option for this aggressive breast cancer subtype. The good news, however, is that TNBC is also the most immune-infiltrated among breast tumors, meaning it attracts more immune cells than other breast cancer types. This suggests that the interaction between immune and tumor cells may play an important role—and that immunotherapy might be effective. Although single-agent immunotherapies proved largely ineffective in early testing, subsequent studies showed that combining chemotherapy with immunotherapy improved outcomes in both early-stage and advanced TNBC. Despite these advances, many patients do not derive the expected benefit from immunotherapy, and doctors still do not know exactly how to identify them in advance. This article reviews the data for immunotherapy in TNBC, along with the questions and challenges that remain. ## Understanding TNBC and the Immune System To understand why immunotherapy works in TNBC, it helps to know a bit about how the immune system fights cancer. Immune cells called T-cells are constantly on the lookout for abnormal cells, including cancer cells. However, cancer cells can develop ways to hide from or disable these immune cells. One common trick is to express a protein called PD-L1 on their surface, which binds to a receptor called PD-1 on T-cells. This binding acts like a "brake," telling the T-cell to stand down and not attack. Immune checkpoint inhibitors—the drugs at the center of this article—work by releasing that brake. Drugs like pembrolizumab (Keytruda) and atezolizumab (Tecentriq) block the interaction between PD-1 and PD-L1, allowing the immune system to recognize and attack the cancer. Because TNBC tends to have more immune cells infiltrating the tumor than other breast cancer types, researchers hypothesized that these drugs might be particularly effective in this subtype. ## Immunotherapy for Early-Stage TNBC: The Evidence Historically, treatment of early-stage TNBC (eTNBC) relied on chemotherapy administered as a sequence of multiple drugs before or after surgery. Although giving chemotherapy before surgery (neoadjuvant chemotherapy) was never shown to improve outcomes over giving it after surgery (adjuvant chemotherapy), it offers clinical advantages: doctors can assess how the tumor responds in the living body, which helps with risk stratification and guides treatment decisions after surgery. Achieving a pathologic complete response (pCR)—meaning no cancer cells remain at the time of surgery—correlates with excellent long-term outcomes and is now an established surrogate endpoint (a stand-in measure that predicts long-term benefit) in this setting. ### The Landmark KEYNOTE-522 Trial In 2021, the results of the KEYNOTE-522 (KN522) trial demonstrated the value of adding immunotherapy to chemotherapy as neoadjuvant treatment for stage 2 and 3 early-stage TNBC. This was a phase III, randomized trial that compared pembrolizumab plus a 4-drug chemotherapy regimen (carboplatin-paclitaxel followed by epirubicin-cyclophosphamide [EC] or adriamycin-cyclophosphamide [AC]) to chemotherapy alone. After surgery, patients in the immunotherapy group continued pembrolizumab to complete a full year of treatment. The results were striking: - Adding pembrolizumab increased the pCR rate from 51.2% to **64.8%** (P<0.001), meaning nearly two-thirds of patients had no cancer detectable at surgery. - The 3-year event-free survival (EFS)—the time patients lived without cancer returning or worsening—improved to **84.5%** in the experimental arm versus 76.8% in the control arm (hazard ratio [HR] 0.63, P=0.0003). - The updated analysis, although not yet published, reported a slightly lower pCR difference (63% vs 55.6%). - In PD-L1 positive tumors, pCR was 68.9% with pembrolizumab versus 54.9% without; in PD-L1 negative tumors, the pCR was 45.3% versus 30.3%. - Three-year overall survival (OS) was 89.7% in the pembrolizumab arm versus 86.9% in the control arm (HR 0.72, P=0.032). ### Other Trials: Mixed but Informative Results Trials with other immune checkpoint inhibitors have yielded less straightforward results, highlighting just how much remains to be learned. **GeparNuevo:** This phase II trial investigated nanoparticle albumin-bound paclitaxel (nab-paclitaxel) followed by EC, with or without the immunotherapy drug durvalumab. The study did not significantly improve the primary endpoint of pCR (53.4% vs 44.2%; odds ratio [OR] 1.45; P=0.287). However, it did show a benefit in invasive disease-free survival (iDFS)—the time until invasive cancer returns—with a 3-year iDFS of 84.9% versus 76.9% (HR 0.54, P=0.0559). It also showed an overall survival (OS) benefit: 3-year OS was 95.1% versus 83.1% (HR 0.26, P=0.0076), although the study was not designed (powered) to detect survival differences. **NeoTRIP:** In this phase III study, the combination of atezolizumab plus carboplatin and nab-paclitaxel did not improve pCR over carboplatin plus nab-paclitaxel alone (48.6% vs 44.4%; OR 1.18; P=0.48). The primary endpoint, event-free survival, had not yet been reported at the time of this review. Notably, in PD-L1 positive tumors, pCR was 59.5% with atezolizumab versus 51.9% without; in PD-L1 negative tumors, pCR was 33.9% versus 35.4%. **IMpassion031:** This study investigated nab-paclitaxel followed by AC, with or without atezolizumab, and met its primary endpoint. The pCR rate was significantly higher with immunotherapy: **57.6% versus 41.1% (P=0.0044)**. There was also a trend toward longer event-free survival (EFS HR 0.76, 95% CI 0.40–1.44; OS HR 0.69, 95% CI 0.25–1.87), though the study was not powered for survival analyses. In PD-L1 positive tumors, pCR was 68.8% versus 49.3%; in PD-L1 negative tumors, it was 48% versus 34%. **GeparDouze:** This ongoing phase III trial (NCT03281954) is testing the same atezolizumab-based regimen as IMpassion031 but with the addition of carboplatin in combination with nab-paclitaxel. The estimated primary completion date is December 31, 2023. Results were not yet available at the time of publication. In summary, immunotherapy can be active in patients with early-stage TNBC, but these conflicting results highlight how many questions remain about the best way to use these drugs. ## Which Chemotherapy Works Best With Immunotherapy? The KEYNOTE-522 regimen uses a maximum number of chemotherapy agents: sequential paclitaxel/carboplatin followed by an anthracycline/cyclophosphamide combination. But whether this is truly the best "chemotherapy backbone" remains unclear. Anthracyclines have traditionally been the cornerstone of (neo)adjuvant therapy for high-risk TNBC. However, these agents carry risks of potentially severe long-term side effects, including **cardiac failure** and **secondary hematologic malignancies** (blood cancers caused by treatment). Yet when combined with immunotherapy, anthracyclines seem to be particularly effective. Evidence supporting anthracyclines includes: - The phase II TONIC trial, which compared different induction strategies in patients with metastatic TNBC (mTNBC), showed the highest objective response rate with the anthracycline doxorubicin (35%). - The NeoTRIP trial, which did not use anthracyclines before surgery, failed to show a pCR improvement, suggesting that anthracyclines might be needed to boost immunotherapy activity. However, there is also evidence suggesting not all patients need anthracyclines: - Data from the pembrolizumab-only arm of the I-SPY2 study showed an equal estimated pCR rate (27%) for paclitaxel followed by AC compared with pembrolizumab plus paclitaxel followed by pembrolizumab alone—though both rates were low. - The recently presented phase II NeoPACT trial showed an impressive pCR rate of **58%** with carboplatin plus docetaxel and pembrolizumab, and a 2-year EFS of **89%**. Despite the limitations of both trials—the I-SPY2 analysis closed prematurely due to lack of activity, and NeoPACT was a small, single-arm study—these findings suggest that not all patients require anthracyclines. At present, administering anthracyclines as part of the KEYNOTE-522 regimen is standard practice. Nevertheless, these data are reassuring for patients who cannot tolerate anthracyclines or who have medical contraindications to them. ### The Platinum Question KEYNOTE-522 notably included platinum chemotherapy (carboplatin) as part of the regimen, even though platinum was not universally recommended to all patients before this trial due to inconclusive neo/adjuvant data. Three major trials investigated adding platinum to various chemotherapy regimens. Although all three demonstrated a pCR benefit, the disease-free survival advantage observed in the BrighTNess and GeparSixto trials was not seen in the CALGB 40603 study. Interestingly, in the I-SPY2 trial, patients receiving pembrolizumab plus paclitaxel followed by EC/AC—the same chemotherapy backbone as KEYNOTE-522 but *without platinum* and with lower pembrolizumab exposure—achieved a pCR rate of 60%, only slightly inferior to the 64.8% seen in KEYNOTE-522. Moreover, the EFS observed in GeparNuevo and KEYNOTE-522 were very similar, despite the fact that GeparNuevo did not include platinum and administered immunotherapy only before surgery. Inclusion of platinum in neoadjuvant therapy for early-stage TNBC is thus controversial. Although it is recommended for patients with high-risk tumors (node-positive, stage III), it is not standard practice for most stage II tumors, where case-by-case management is preferred. Platinum is also frequently responsible for severe myelotoxicity (suppression of bone marrow function), which may compromise dose intensity. For patients with poor tolerance, early withdrawal of platinum can be considered. ## Timing and Sequencing: Before or After Surgery? Whether immunotherapy should be given before or after surgery is unknown. Three large, phase III trials are currently investigating immunotherapy in the adjuvant (post-surgery) setting: - **SWOG S1418 (NCT02954874):** A randomized, open-label, phase III trial with 1,155 patients who have residual disease after neoadjuvant therapy (TNBC with ER/PR ≤5%, residual disease ≥1 cm and/or positive lymph nodes). Patients receive 1 year of pembrolizumab versus observation. - **IMpassion030/ALEXANDRA (NCT03498716):** A randomized, open-label, phase III trial with 2,300 patients with stage II–III TNBC, testing weekly paclitaxel/dose-dense AC with or without atezolizumab, followed by maintenance atezolizumab. - **A-BRAVE (NCT02926196):** A randomized, open-label, phase III trial with 474 patients. Stratum A includes patients after adjuvant chemotherapy for stage IIB–III TNBC; Stratum B includes patients with residual disease after neoadjuvant therapy. Treatment is avelumab versus observation. None of these studies will answer the question of whether neoadjuvant immunotherapy should be continued in the adjuvant setting after surgery. Following the KEYNOTE-522 study, pembrolizumab is now routinely continued for an additional 27 weeks (about 6 months) in all patients, even though patients who achieve a pCR are likely to derive little benefit, given the excellent outcomes of pCR patients in both arms. Whether pembrolizumab should be continued after a pCR is therefore a matter of debate. Other studies suggest that omitting adjuvant immunotherapy may have little impact on outcomes. In the GeparNuevo trial, durvalumab was administered only in the neoadjuvant setting and had similar long-term outcomes to KEYNOTE-522. Similarly, the 2-year EFS in the NeoPACT study was 89%, despite the fact that only 4% of patients received adjuvant pembrolizumab. A planned trial called **OptimICE-pCR**, led by the Alliance cooperative group, hopes to randomize patients who achieve a pCR after preoperative pembrolizumab/chemotherapy to receive adjuvant pembrolizumab or not. Patients with residual disease (cancer that remains after neoadjuvant therapy) seemed to derive the greatest benefit from pembrolizumab in the KEYNOTE-522 trial—although this comes from an exploratory, post-hoc analysis that was not controlled for multiplicity (meaning the finding could be due to chance given the many analyses performed). Additionally, the use of other currently approved post-neoadjuvant agents, such as capecitabine or olaparib, was not allowed in the trial protocol. In 2017, shortly after the KEYNOTE-522 trial started, the CREATE-X study showed a survival benefit with the addition of capecitabine in the setting of residual disease after neoadjuvant therapy for early-stage TNBC. More recently, the OlympiA trial proved that 1 year of adjuvant olaparib (a PARP inhibitor) leads to improvements in both disease-free survival and overall survival in high-risk, germline BRCA carriers with early-stage TNBC after both adjuvant and neoadjuvant chemotherapy. Despite these controversies, pembrolizumab is generally continued after surgery—in combination with either capecitabine or olaparib for patients with residual disease—because safety data from the metastatic setting showed that combining checkpoint inhibition with these agents is safe. Finally, the optimal sequencing strategy between immunotherapy and chemotherapy remains unknown. In the GeparNuevo study, a subset of patients in the experimental arm received a 2-week "run-in" of durvalumab alone before starting chemotherapy. Notably, this was the only subset in which a pCR benefit was observed. Although differences in patient and tumor characteristics between the window and non-window cohorts might explain the difference in response, a priming immunologic effect of durvalumab alone cannot be excluded. ## Biomarkers in Early-Stage Disease: Who Benefits Most? Many correlative studies have investigated different biomarkers in patients receiving chemotherapy plus immunotherapy, but none has definitively identified which patients derive significant benefit specifically from the immunotherapy component. In the KEYNOTE-522 study, programmed cell death-ligand 1-positive (PD-L1+) tumors showed a higher pCR rate than PD-L1-negative (PD-L1−) tumors, irrespective of treatment arm—but the benefit of immunotherapy was consistent in both PD-L1+ and PD-L1− tumors. A similar finding emerged from the IMpassion031 study, where the benefit from adding atezolizumab was independent of PD-L1 expression. In contrast, the NeoTRIP trial showed a significantly higher benefit from immunotherapy only in PD-L1+ breast cancer. The reason for this discrepancy is unknown, but differences in the chemotherapy backbone—notably the absence of anthracyclines in NeoTRIP—or the proportion of immune cells (IC 1+ versus 2+/3+) have been offered as potential explanations. The prognostic and predictive role of **tumor-infiltrating lymphocytes (TILs)**—immune cells that have penetrated the tumor—has also been widely explored. High TILs have been shown to correlate with excellent long-term outcomes in patients with TNBC receiving chemotherapy alone, and even in patients treated with surgery alone, highlighting the crucial role of immune surveillance in TNBC. A correlation between TILs and higher pCR has also been observed across trials investigating chemotherapy plus immunotherapy combinations, although findings about a predictive role for immunotherapy benefit have been conflicting: - In the GeparNuevo study, stromal TILs (sTILs) were shown to independently predict pCR in both arms. - In the NeoTRIP study, baseline sTILs were found to correlate with higher pCR only in the atezolizumab arm. - In the NeoPACT study, an impressive pCR rate of **76%** was observed in tumors with sTILs greater than or equal to 30%, which represented 48% of cases. - sTILs were also assessed at cycle 2 in the NeoTRIP study, where they strongly correlated with pCR in both arms. Of note, a significant arm imbalance of TILs favoring the chemotherapy-only arm was noticed in the NeoTRIP trial, and investigators claimed this difference was a potential reason for the lack of pCR benefit. Several other immune-related biomarkers have been investigated, including immune-associated gene signatures and tumor mutational burden (TMB). Most have proven to be highly intercorrelated, and none has been shown to specifically predict immunotherapy benefit. ## Immunotherapy for Advanced-Stage TNBC Phase I trials investigating immune checkpoint inhibitors in patients with previously treated metastatic TNBC (mTNBC) failed to show important benefit. Nevertheless, signs of activity were seen in less heavily pretreated patients with PD-L1+ tumors, suggesting that different patient selection might define cohorts who benefit from immunotherapy. The use of concurrent immunotherapy plus chemotherapy in first-line treatment of metastatic TNBC has been shown to favorably affect outcomes. ### The KEYNOTE-355 Trial KEYNOTE-355 (KN355) was a randomized, phase III study that investigated the addition of pembrolizumab to chemotherapy versus chemotherapy alone in patients with treatment-naïve metastatic TNBC. Patients could receive one of three chemotherapy options: nab-paclitaxel, paclitaxel, or carboplatin-gemcitabine. Patients were stratified according to PD-L1 expression, as assessed by the combined positive score (CPS) using the 22C3 antibody test. The trial had two primary endpoints: progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population and in patients with PD-L1+ tumors (defined as CPS ≥10 and CPS ≥1). Key results: - A statistically significant benefit was observed for PD-L1+ (CPS ≥10) tumors in terms of both PFS (HR 0.65; P=0.0012) and OS (HR 0.73; P=0.0093). - There was no significant difference for PD-L1− breast cancer. - No heterogeneity was observed for the three chemotherapy backbones, with a slightly higher benefit from taxanes (paclitaxel-type drugs) emerging from the subgroup analysis. - However, caution is needed when interpreting these data—patients were not randomized to a specific chemotherapy agent, and physicians were more likely to choose carboplatin plus gemcitabine in patients experiencing early relapse. ### The Atezolizumab Story: IMpassion130 and IMpassion131 Data investigating atezolizumab in the same setting have been controversial. **IMpassion130** was a phase III, randomized study investigating the addition of atezolizumab to first-line nab-paclitaxel. The trial was positive for PFS in the ITT population (a co-primary endpoint), with a median PFS of 7.2 versus 5.5 months (HR 0.80, P=0.0025), and in the PD-L1+ subgroup (7.5 vs 5.0 months; HR 0.62, P<0.001). A clinically meaningful benefit in OS in PD-L1+ patients was also observed (25.4 vs 17.9 months; HR 0.67), although due to the analytical plan of the trial, this was not statistically significant. **IMpassion131**, a very similar phase III trial, investigated paclitaxel with or without atezolizumab and showed *no benefit* from adding the immunotherapy drug, even in PD-L1+ patients. Several reasons for these discrepancies have been hypothesized, including the need for steroids with paclitaxel (which may suppress immune activity), and the unprecedented OS outcome observed with paclitaxel alone in the control arm. Although atezolizumab was granted accelerated approval for TNBC in 2019 based on the IMpassion130 study, the negative findings from IMpassion131 led the company to withdraw the drug's indication in the United States. This history underscores how fragile drug approvals can be when later trials fail to confirm earlier results. ## Treatment Duration, Sequencing, and Later Lines of Therapy Duration of immunotherapy is an important consideration in metastatic TNBC. As in other tumor types, there are some long-term responders with metastatic TNBC who derive benefit from immunotherapy lasting many years. Indeed, around **28%** of patients with metastatic TNBC and PD-L1 CPS greater than 10 who received immunotherapy in the KEYNOTE-355 study were progression-free at 2 years. This compares favorably to the approximately 30% to 37% rate seen with first-line anti-PD1 monotherapy for melanoma, and the approximately 20% rate with first-line chemo-immunotherapy for non-small cell lung cancer (NSCLC). Evidence from melanoma and NSCLC suggests that stopping treatment after 2 years should be safe, but evidence in breast cancer is lacking. This is an important area of ongoing research, as longer treatment means more time dealing with potential side effects and more cost to the healthcare system. In parallel, trials are investigating whether a different sequence—chemotherapy first, followed by maintenance immunotherapy—might be beneficial. From a biological standpoint, a priming chemotherapy phase may promote tumor immunity through two mechanisms: the induction of **immunogenic cell death** (ICD), a form of cell death that triggers an immune response, and the killing of suppressive immune cells. The SAFIR-02 trial investigated the administration of maintenance durvalumab after chemotherapy in HER2-negative advanced breast cancer. The trial was negative in the intention-to-treat population but showed a significant advantage in the TNBC subgroup (n=82, median survival 14.0 vs 21.2 months, HR 0.54; P=0.04) and in PD-L1+ tumors (12.1 vs 25.8 months, HR 0.42; P=0.06). Alternative maintenance strategies combining immunotherapy with targeted agents or chemotherapy after a chemotherapy-only phase are under investigation. Little is known regarding the best second-line treatment for progression following first-line immunotherapy-based treatment. At present, there is **no role for continuing immunotherapy beyond overt disease progression**—meaning once a tumor clearly starts growing again, continuing the immunotherapy is not recommended. ## Biomarker Testing Challenges in Advanced Disease Although expression of PD-L1 by tumor and immune cells predicts immunotherapy benefit for patients with metastatic TNBC, PD-L1 is far from a perfect biomarker for patient selection. Different studies have relied on distinct assays to assess PD-L1. The KEYNOTE trials used the **Dako 22C3 assay** and applied the **combined positive score (CPS)** to define PD-L1 positivity. The CPS is calculated by counting the number of PD-L1-staining cells (including tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells, multiplied by 100. In contrast, the IMpassion trials used the **Ventana SP142 assay** and the **immune score (IC)**, which is defined by the proportion of tumor area occupied by PD-L1-staining immune cells of any intensity. Other assays and scoring criteria are also available. A re-analysis of samples from the IMpassion130 study showed a poor inter-assay overlap, with only moderate concordance between the SP142, SP263 (Ventana), and 22C3 (Dako) assays (Spearman correlation coefficient r=0.57–0.69). Nevertheless, the correlation with clinical activity was similar across assays (PFS HR 0.60–0.68; OS HR 0.74–0.79). Interestingly, the CPS cutoff that best reflected the PD-L1+ population as defined by SP142 was 10—the same cutoff that was shown to predict benefit from pembrolizumab in the KEYNOTE-355 study. Perhaps more critically, PD-L1 is a **dynamic biomarker**: its expression changes over time and across different metastatic sites. Higher rates of PD-L1+ tumors are usually observed in primary (original) tumor samples versus metastatic (spread) samples, and PD-L1 positivity is especially low in particular metastatic sites such as the liver, skin, and bone. Of note, all samples for PD-L1 assessment in the KEYNOTE-355 trial were from metastatic sites, whereas the IMpassion130 trial allowed both primary and metastatic samples. This difference in sampling could contribute to the different results seen across trials. ## Clinical Implications: What This Means for Patients For patients with early-stage TNBC, the combination of immune checkpoint inhibitors and chemotherapy is now the **new standard of care** in both the early-stage and first-line metastatic settings. The KEYNOTE-522 regimen—pembrolizumab plus carboplatin-paclitaxel followed by anthracycline/cyclophosphamide, then continued pembrolizumab after surgery to complete one year—has become a cornerstone of treatment for stage 2 and 3 disease. What this means in practical terms: - Patients with early-stage TNBC now have a treatment option that meaningfully increases their chance of having no cancer remaining at surgery (pCR), which translates to better long-term outcomes. - Patients with metastatic TNBC whose tumors are PD-L1 positive (CPS ≥10) can benefit from adding pembrolizumab to first-line chemotherapy, with a significant improvement in both progression-free and overall survival. - Patients who cannot tolerate anthracyclines may have reassuring alternatives, though anthracyclines remain standard in the KEYNOTE-522 regimen. - Patients with residual disease after neoadjuvant therapy may consider combining adjuvant pembrolizumab with capecitabine or olaparib (in BRCA carriers), based on safety data from the metastatic setting. ## Limitations: What the Research Cannot Yet Answer It is important for patients to understand that many questions remain unanswered, even as immunotherapy becomes standard of care: - **The ideal chemotherapy backbone is unknown.** The KEYNOTE-522 regimen uses many chemotherapy drugs, and it is unclear whether all are necessary or whether anthracyclines specifically are required for the immunotherapy to work best. - **Optimal sequencing is unclear.** Whether immunotherapy should be given before surgery, after surgery, or both, is still being studied. The ongoing SWOG S1418, IMpassion030, and A-BRAVE trials are investigating the adjuvant-only approach. - **Predictive biomarkers are lacking.** PD-L1 testing is imperfect, and different assays give different results. TILs show promise but are not yet validated for routine clinical decision-making in this setting. - **Not all patients benefit.** Even in the successful trials, a substantial proportion of patients did not achieve a pCR or long-term survival benefit. Identifying these patients in advance is an urgent research priority. - **Treatment beyond progression is not recommended.** Little is known about the best second-line treatment after first-line immunotherapy-based therapy. - **The 2-year stopping rule is unproven in breast cancer.** Evidence from melanoma and lung cancer suggests stopping after 2 years is safe, but breast cancer-specific data do not yet exist. ## Recommendations for Patients Based on this review, here are key points patients may wish to discuss with their oncology team: 1. **Ask about immunotherapy if you have early-stage TNBC.** If you have been diagnosed with stage 2 or 3 TNBC and are planning neoadjuvant chemotherapy, ask whether pembrolizumab plus chemotherapy (the KEYNOTE-522 regimen) is appropriate for you. 1. **Request PD-L1 testing if you have metastatic TNBC.** PD-L1 status (using the CPS score with the 22C3 assay) helps determine whether adding pembrolizumab to first-line chemotherapy will be beneficial. Make sure you know which test was used and what your score means. 1. **Ask about clinical trials.** Several important trials are actively investigating adjuvant immunotherapy, de-escalation strategies (such as the OptimICE-pCR trial), and new combination approaches. Participating in a clinical trial may give you access to promising new treatments. 1. **Discuss chemotherapy backbone options.** If you have medical reasons to avoid anthracyclines (such as pre-existing heart conditions) or platinum agents (such as concerns about bone marrow toxicity), ask your doctor about the evidence for alternative regimens. A case-by-case approach may be appropriate for stage II tumors. 1. **Talk about side effects.** Immunotherapy can cause immune-related side effects—inflammation of the lungs (pneumonitis), colon (colitis), liver (hepatitis), thyroid, or other organs. Knowing the warning signs and reporting symptoms early is important for managing these risks. 1. **Understand the goals of treatment.** In the early-stage setting, the goal is cure, and the pCR rate improvement from approximately 51% to 65% represents a meaningful advance. In the metastatic setting, the goal is extending life and maintaining quality of life, with a subset of patients achieving durable long-term benefit. ## Frequently Asked Questions ### What is immunotherapy for triple-negative breast cancer, and how does it work? Immunotherapy uses drugs called immune checkpoint inhibitors, such as pembrolizumab or atezolizumab, to help your immune system attack cancer cells. These drugs block the PD-1/PD-L1 interaction that acts like a brake on T-cells, allowing the immune system to recognize and fight the tumor. In TNBC, combining immunotherapy with chemotherapy has improved outcomes in both early and advanced stages. ### Who is eligible for immunotherapy in early-stage triple-negative breast cancer? For early-stage TNBC, the KEYNOTE-522 regimen—pembrolizumab plus chemotherapy before surgery, followed by pembrolizumab after surgery—is standard for stage 2 or 3 disease. This is typically recommended when you are planning neoadjuvant chemotherapy. Your doctor will determine if this approach is appropriate based on tumor stage, health status, and other factors. Ask your oncology team about eligibility. ### What does pathologic complete response (pCR) mean, and why is it important? A pathologic complete response means no cancer cells are found at the time of surgery after neoadjuvant treatment. Achieving pCR correlates with excellent long-term outcomes. In the KEYNOTE-522 trial, adding pembrolizumab increased the pCR rate from 51.2% to 64.8%, meaning nearly two-thirds of patients had no cancer detectable at surgery. ### Will I need PD-L1 testing if I have metastatic triple-negative breast cancer? Yes. For metastatic TNBC, PD-L1 status helps determine whether adding pembrolizumab to first-line chemotherapy will be beneficial. The test uses the combined positive score (CPS) with the 22C3 assay. In the KEYNOTE-355 trial, patients with CPS ≥10 had significant improvements in progression-free and overall survival. Ask your doctor which test was used and what your score means. ### What are the possible side effects of immunotherapy for breast cancer? Immunotherapy can cause immune-related side effects, including inflammation of the lungs (pneumonitis), colon (colitis), liver (hepatitis), or thyroid. It is important to know the warning signs and report symptoms early. Side effects can be managed with medications, but prompt attention is crucial. Your oncology team will monitor you closely during treatment. ### Is immunotherapy recommended after surgery for early-stage TNBC? In the KEYNOTE-522 regimen, pembrolizumab is continued for additional weeks after surgery to complete one year of treatment. However, whether this is necessary for all patients is debated, especially for those who achieved a pCR. Ongoing trials are studying this question. For patients with residual disease, doctors may combine pembrolizumab with capecitabine or olaparib based on safety data. ### How effective is immunotherapy in advanced triple-negative breast cancer? In metastatic TNBC, adding pembrolizumab to first-line chemotherapy improved survival for patients with PD-L1 positive tumors (CPS ≥10). In the KEYNOTE-355 trial, the benefit was significant for progression-free and overall survival. About 28% of these patients were progression-free at 2 years. But immunotherapy is not effective for everyone, and PD-L1 negative tumors showed no significant benefit. ## Source Information **Original article:** "Role of Immunotherapy in Early- and Late-Stage Triple-Negative Breast Cancer" by Stefania Morganti, MD, and Sara M. Tolaney, MD, MPH. **Publication:** Hematology/Oncology Clinics of North America, Volume 37, Issue 1, pages 133–150, February 2023. Published by Elsevier Inc. DOI: https://doi.org/10.1016/j.hoc.2022.08.014 **Affiliations:** Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA; Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Boston, MA; Department of Oncology and Hemato-Oncology, University of Milan, Istituto Europeo di Oncologia, Milan, Italy. *Note: This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace individualized medical advice from your oncology team. Treatment decisions should always be made in consultation with qualified healthcare professionals who know your specific medical situation.* --- Publisher: Diagnostic Detectives Network (https://diagnosticdetectives.com) — independent multi-expert medical second opinions, worldwide, private-pay. Author byline: Anton Titov, MD, PhD. Contact: https://diagnosticdetectives.com/pages/contact Canonical page: https://diagnosticdetectives.com/products/immunotherapy-for-triple-negative-breast-cancer-what-patients-need-to-know