The Evolving Landscape of Immunotherapy in Breast Cancer

For decades, breast cancer was clinically categorized as an immunologically “cold” malignancy, characterized by a low tumor mutational burden and a sparse immune microenvironment. However, the therapeutic landscape is undergoing a radical transformation. From the initial signals of activity in the phase 1 KEYNOTE-012 study (NCT01848834) to the establishment of chemoimmunotherapy as a frontline standard in metastatic triple-negative breast cancer (TNBC), the oncology community is now navigating a complex era of precision immunology.¹

In this interview, Sarah Poland, MD, a third-year fellow at the University of Chicago Medicine, expanded on her recently review published in ONCOLOGY®, “Advances in Immunotherapy for Breast Cancer.”² Poland and co-authors provided a clinician-focused analysis of the “turning points” in breast cancer research, including the critical lessons learned from the withdrawal of atezolizumab (Tecentriq) and the promising emergence of immunotherapy in hormone receptor (HR)-positive and HER2-positive subtypes.

Beyond traditional checkpoint inhibition, Poland addressed the practical challenges facing today’s oncologists:

• Navigating PD-L1–Negative Disease: Exploring the role of antibody-drug conjugates (ADCs) like sacituzumab govitecan-hziy (Trodelvy) and datopotamab deruxtecan-nlnk (Dato-DXd; Datroway) for patients ineligible for immunotherapy.
• Toxicity Management: Strategies for mitigating unique immune-related adverse events (irAEs) while maintaining therapeutic efficacy.
• Treatment De-escalation: Evaluating whether patients who achieve a pathologic complete response (pCR) can safely omit adjuvant immunotherapy.
• Future Frontiers: The clinical readiness of bispecific antibodies and the potential of novel ADC-immunotherapy combinations.

CancerNetwork: Breast cancer was historically considered a cold or poorly immunogenic type of cancer. What do you believe was the most critical turning point in clinical research that shifted this perspective for the oncology community?

Poland: When immunotherapy was initially being studied, breast cancer was not one of the most exciting types of cancer that they were looking to treat with this type of new therapy. There are multiple reasons for that. In prior research, particularly in the laboratory, breast cancer wasn’t one of the types of cancer that seemed the most immunologically active, that seemed like it had the highest tumor mutational burden or an immune microenvironment around the tumor that seemed to have a high proportion of tumor-infiltrating lymphocytes or things that would lend to it being a good candidate for immunotherapy. When we saw other malignancies being treated with immunotherapy, such as melanoma, which has traditionally been difficult to treat, especially in the metastatic setting, there became a lot of excitement for all different types of cancers in oncology.

Particularly for TNBC, given the lack of targetable mutations—for example, HR-positive breast cancer—we’re able to target the estrogen receptor for HER2-positive breast cancer [and] we’re able to target the HER2 receptor. For TNBC, for a long time, we didn’t have a lot of answers beyond traditional chemotherapy, so there was a lot of interest in utilizing this subtype, particularly as a potential option for immunotherapy. As we mentioned in the review, the KEYNOTE-012 study was the first study to evaluate pembrolizumab [Keytruda] monotherapy.

Pembrolizumab is a PD-1–blocking antibody and a type of immunotherapy in PD-L1–positive tumors. The fact that there was an 18.5% overall response rate, as well as multiple patients who had some long-lasting responses to pembrolizumab, was a turning point for us. It changed opinions on whether it could be possible to treat breast cancer in this way and laid the foundation for a lot of our immunotherapy trials that we go on to discuss further in the review.

Based on the KEYNOTE-355 data, pembrolizumab plus chemotherapy is now standard for first-line metastatic TNBC with a CPS of 10 or more. How should clinicians navigate treatment for the population that is PD-L1–negative or has a CPS of less than 10?

For first-line metastatic TNBC with a PD-L1 [combined positive score (CPS)] of less than 10, standard of care has been chemotherapy upfront for metastatic treatment, as pembrolizumab did not end up getting approved for CPS less than 10 per the phase 3 KEYNOTE-355 trial [NCT02819518].³ In addition, you can also use PARP inhibitors as a first-line option for anybody with a germline BRCA1/2 mutation. This has been what we’ve been working with for this patient population for a number of years, because we haven’t been able to use immunotherapy. With the advent of ADCs, we have seen some new agents potentially being able to move into the frontline metastatic setting for TNBC, particularly for those patients who are not eligible for immunotherapy. The phase 3 ASCENT-03 study [NCT05382299] showed improved progression-free survival for sacituzumab govitecan compared with chemotherapy in patients with advanced or metastatic TNBC who weren’t candidates for immunotherapy.⁴

The phase 3 TROPION-Breast02 trial [NCT05374512] looked at another ADC, Dato-DXd, and that showed improved progression-free survival and overall survival, as compared with chemotherapy, in those patients in that PD-L1–negative population not eligible to get immunotherapy in the front line.⁵ Both trials were presented at the European Society for Medical Oncology [in 2025], and they offer some potential new avenues for treatment for frontline, advanced or metastatic TNBC with a CPS less than 10. As of right now, our standard of care is still going to be chemotherapy or potentially PARP inhibitors for our patients with BRCA [mutations], but we’re starting to see some new and exciting options, particularly for that patient population.

The review also discussed the withdrawal of atezolizumab’s FDA approval for the metastatic TNBC setting following the IMpassion trials. What are some primary takeaways for clinicians regarding the differences in trial design and chemotherapy backbones?⁶

These are some interesting trials to think about, particularly because their outcomes were so different. There was excitement around atezolizumab initially being FDA-approved. The IMpassion trials investigated a PD-L1–blocking agent called atezolizumab, and the phase 3 IMpassion-130 trial [NCT02425891] showed an increase in overall survival, and that led to the accelerated FDA approval for atezolizumab.⁷ However, the phase 3 follow-up trial, IMpassion-131 [NCT03125902], was negative.⁸ It didn’t show a significant improvement in progression-free survival in the intention-to-treat population, and atezolizumab didn’t improve overall survival, which was also an important secondary end point. That was in the intention-to-treat population, and they even looked specifically in the PD-L1–positive patient population. They again did not see an improvement. That leads us, as a breast cancer and oncology community, to try to figure out why they seemed so different.

You want to look at the baseline patient populations between the 2 trials. Looking at the demographics, they were very similar. [You also want to] look at the control arms to see if they maybe performed differently or even better than expected, particularly in the IMpassion-131 trial, [which] was negative. Looking at the median progression-free survival in the control arms, it was similar between the 2 trials: 5.6 months and 5.5 months between the 2 [arms]. However, the median overall survival was quite different, especially in the [PD-L1–positive] patient population in IMpassion-131, which was our negative trial. The median overall survival was 28.3 months with the paclitaxel group vs 17.9 months with the nab-paclitaxel group in the positive trial, IMpassion-130. That does lend itself to the thinking, “Could there maybe have been a longer overall survival in a control group than we expected?” As I just mentioned, there were different chemotherapy backbones—paclitaxel as compared with nab-paclitaxel—and paclitaxel does require a steroid pre-medication.

There were some conversations around [whether] giving steroids prior to the immunotherapy could potentially blunt an immune response. That’s still debatable. KEYNOTE-355 was a positive trial, and it did investigate pembrolizumab with nab-paclitaxel, paclitaxel, and gemcitabine and carboplatin. There was no evidence, at least from that trial, that paclitaxel performed worse than nab-paclitaxel. Overall, this is just an important lesson that these trials show how important it is to do confirmatory trials, especially when you get that accelerated FDA approval, just to make sure that we’re giving the most appropriate and best options to our patients.

While TNBC has the most established data, you note that emerging evidence is available in other subtypes. In what specific HR-positive or HER2-positive clinical scenarios are you most optimistic about the role of immunotherapy?

This is an area that’s exciting, but where we don’t have the ability to use immunotherapy yet. Looking at some of the ongoing trials, the trials that have already read out and been completed give us a hint of where we could expect to see immunotherapy used for our patients who are HR-positive, as well as [those who are] HER2-positive. Looking at the subtypes that we’re the most excited about outside of TNBC, specifically for HR-positive disease, as we highlight in the review article, the higher risk luminal B subtype of HR-positive disease, lower progesterone receptor, a high Ki67 index, and a high grade would be thought to behave more like TNBC and potentially respond better to immunotherapy.

One trial that we do talk about is the phase 3 KEYNOTE-756 trial [NCT03725059]. It explored utilizing immunotherapy in estrogen receptor-positive, HER2-negative [stage] III breast cancer, and compared neoadjuvant immunotherapy—pembrolizumab vs placebo—combined with our traditional chemotherapy backbone, paclitaxel, and then anthracycline/[cyclophosphamide], and patients then also got adjuvant pembrolizumab.⁹

This was a similar study design to the phase 3 KEYNOTE-522 trial [NCT03036488] for TNBC.¹⁰ When they looked at the results, the pCR is something that’s important for our neoadjuvant trials. It did show that the pCR rate was higher in the pembrolizumab/chemotherapy arm than the chemotherapy arm alone. Looking at specifically the subgroups of this HR–positive patient population, the tumors that had a higher PD-L1 expression and an [estrogen receptor (ER)] less than about 10% did better. They responded better to the immunotherapy, and they also did have an exploratory end point for RCB status, or residual cancer burden, so essentially how much tumor was left for the patients who didn’t achieve that? pCR can be very important in looking at recurrence rates and overall survival for those patients. [The study] did find that the immunotherapy shifted more patients to a lower RCB category.

Similarly, the other trial that we talked about for patients who were HR-positive with immunotherapy in the review article is the phase 3 CheckMate 7FL trial [NCT04109066]. It did show that a higher pCR was reported in patients with higher risk, higher grade ER-positive, HER2-negative breast cancer who got nivolumab [Opdivo], which is a different type of immunotherapy.¹¹ It’s an anti–PD-1 plus chemotherapy vs chemotherapy alone. We saw that benefit in a higher PD-L1, ER-low patient population. Those are going to be the clinical scenarios, specifically for HR–positive breast cancer, that we’re the most excited about. Regarding HER2-positive disease, we don’t have immunotherapy in that space yet, but similarly, we’d be looking for tumors with high PD-L1 immune-enriched features, so high tumor infiltrating lymphocytes, thinking that that would lend to a tumor that’s more responsive to immunotherapy. Overall, we’ve seen some mixed results with HER2-positive disease, some positive results from combining immunotherapy with our HER2-targeted therapies—pertuzumab [Perjeta] and trastuzumab [Herceptin]—but others where we haven’t quite seen the same results. This is an area where we’re going to be seeing a lot of research. There are promising subtypes, but again, we need some more definitive, larger phase 3 trials that we can use to drive guideline-directed management.

You and the study authors did mention a key goal of maximizing survival while minimizing toxicity. What is your approach to managing the unique immune-related adverse events when checkpoint inhibitors are combined with traditional cytotoxic chemotherapy?

One of my passions and real research interests is minimizing toxicity for our patients, and that’s incredibly important, because with every new therapy that we get approved in breast cancer, there are new and sometimes unexpected toxicities and [adverse] effects that we need to learn how to manage as an oncology community. There are unique [adverse] effects with immunotherapy, specifically related to the fact that it’s ramping up the immune system, or giving this immune system overactivation. As providers, we have to be vigilant in monitoring for these adverse events. In KETNOTE-355, we saw irAEs in about 27% of patients with pembrolizumab, and higher-grade irAEs in about 5% of those patients. In KEYNOTE-522, for our early-stage patients, we saw about a third of patients having an irAE. Real-world data have reported that maybe even over half of patients develop 1 of these toxicities; the most common types of irAEs are going to be endocrinopathies, such as hyper or hypothyroidism and adrenal insufficiency. Also, skin toxicities can be quite common with this. Most resolve with dose interruption using high-dose steroids. The endocrinopathies are generally irreversible, and they require long-term treatment, usually with hormone or steroid replacement. You can continue to utilize the pembrolizumab for the endocrinopathies, which is something specific to them, which is quite interesting. There are no breast-specific guidelines, but ASCO does have guidelines to outline a strategy for management; usually, it involves some combination of holding treatment and giving high-dose steroids. We can re-challenge if symptoms and lab values typically return to a much lower grade, usually less than grade 1. For more severe events, such as cardiovascular or neurologic irAEs, which can be quite serious, we have a much lower threshold to hold treatment, and we will rechallenge less often, just because it can be so serious and there’s limited evidence. So we’re always monitoring, always talking to the patient and seeing how they're feeling. Checking lab values before every treatment is critical. Remaining very vigilant and making sure that we’re using our steroids and pausing treatment as we need to [is crucial].

You highlighted the ongoing aim to identify the optimal amount and timing of immunotherapy. Are there specific patient populations where you can safely consider de-escalating immunotherapy as an option?

This is an interesting area of research, and one where there are ongoing clinical trials looking at this exact question, because it’s something as a breast cancer community that we’re interested in. I’ve spoken about the KEYNOTE-522 trial a lot already. This is our landmark trial that established the combination of chemoimmunotherapy as the standard of care for stage II to III TNBC. There was a neoadjuvant portion with pembrolizumab and chemotherapy, and there were also 9 cycles of pembrolizumab given post-surgery. Obviously, this was a positive trial. It’s established our standard of care. What the trial didn’t tell us was whether this adjuvant or post-surgical component was necessary. What we did see, when we went back and did some group analyses and further analysis into this trial, was that the patients who [experienced a] pCR, regardless of what arm they were in, regardless of if they got immunotherapy, did much better. In patients who didn't [experience a] pCR, the patients who did get the immunotherapy ended up doing better than those people who only got chemotherapy. This suggests that getting to that pCR is maybe the key part in terms of how our patients will do after this treatment. Maybe the primary driver of how these patients are doing is how they respond to that immunotherapy upfront. There’s thought within the community that adjuvant immunotherapy may not be as effective as neoadjuvant therapy because it’s being given in the neoadjuvant setting before surgery while the tumor is still there, while it’s still intact and while we still have that tumor immune microenvironment to try to ramp up the patient’s own immune system to try to attack. That’s the thought behind why neoadjuvant therapy may be better than adjuvant. This is exactly what the phase 3 OptimICE-pCR trial [NCT05812807], which is ongoing right now, is looking at de-escalating or taking out that post-surgical adjuvant portion of immunotherapy in patients with early-stage TNBC who achieved a pCR after KEYNOTE-522.¹² This is the trial that’s going to provide us some important answers on whether we can de-escalate patients. Which patients are safe to de-escalate? Hopefully this saves patients from some unneeded treatment and potential [adverse] effects, [while also] making sure we’re still getting them the best possible outcome after going through all this therapy.

You identified a combination of ADCs and immunotherapy as an emerging technology. How might these combinations change the sequencing of therapies for patients who have already progressed on that standard of care regimen?

I’ve already mentioned ADCs as a new and exciting therapy that we’re utilizing in a lot of different spaces in breast cancer. They’re one of the most exciting developments in breast cancer care in recent years, either utilizing them alone or even in combination with immunotherapy. As we talk about in the review, sacituzumab govitecan is already approved for later-line treatments of metastatic TNBC, and the OptimICE-pCR trial is currently looking at those patients who [were on] KEYNOTE-522, in the early stage setting, who did not achieve a pCR, who still had residual disease. Looking at one of the arms, adding on that ADC—sacituzumab govitecan—to pembrolizumab—an immunotherapy—after patients got all of that neoadjuvant KEYNOTE-522 chemoimmunotherapy. That’s an exciting trial investigating this combination for our patients.

The phase 3 TROPION-Breast03 trial [NCT05629585] is also looking at a different ADC combination, Dato-DXd combined with durvalumab, which is an anti-PD-L1, vs Dato-DXd alone vs chemotherapy, again for patients with that residual disease after initial treatment.¹³ These combinations are also being investigated in the metastatic setting as well. The phase 3 TROPION-BREAST05 trial [NCT06103864] is investigating Dato-DXd plus durvalumab [Imfinzi] vs Dato-DXd alone vs standard of care, for our patients who are PD-L1-positive.¹⁴ All these trials are investigating ADCs plus immunotherapy for early-stage residual disease or metastatic disease, which is exciting.

We do have, as I mentioned, trials investigating new novel combinations of these ADCs and immunotherapy in later lines, which is promising. One big unanswered question is, “How do we sequence all these new ADCs and immunotherapy combinations? How do we fit this into our standard of care? Do we do ADC after ADC?” That’s one big question that still is out there, and a lot of people are trying to answer it. More research is needed in the space, but we’re going to be seeing more of this for breast cancer treatment.

Beyond PD-1 and PD-L1 blockade, which novel immunogenic agents or technologies, like vaccine trials or bispecific antibodies, do you believe are closest to entering routine clinical practice?

There’s a lot of interest specifically around bispecific antibodies, either alone or in combination with immunotherapy or chemotherapy, that have shown some promise in clinical trials. We mentioned a couple of them in the review, and a few different bispecific antibodies specifically combined with taxane chemotherapy as first-line treatment for metastatic TNBC, both showing a promising overall response rate and a promising progression-free survival. We see a lot of promise for this. We see a lot of excitement for this, but we still don’t know exactly the ideal chemotherapy, or, as I mentioned before, ADC combination with these. What’s the exact patient population that may benefit the most from these new bispecific antibodies? Are there potential biomarkers that would indicate patients who benefit from these bispecifics? They need to be evaluated in larger phase 3 trials before we can definitively start using them. One in particular [that is being] utilized is I-SPY, so we’ll see where it goes in the next couple of years. That’s something that we’re excited about. Vaccine trials have not been as promising for breast cancer specifically. For this reason, the bispecifics are probably closer to entering routine clinical practice and offering some exciting possibilities for breast cancer treatment.

References

1. Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460-2467. doi:10.1200/JCO.2015.64.8931
2. Poland S, de Oliveira Andrade Md M, Nanda R. Advances in immunotherapy for breast cancer. Oncology (Williston Park). 2026;40(1):8-15. doi:10.46883/2026.25921061
3. Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387(3):217-226. doi:10.1056/NEJMoa2202809
4. Cortés J, Punie K, Barrios C, et al. Sacituzumab govitecan in untreated, advanced triple-negative breast cancer. N Engl J Med. 2025;393(19):1912-1925. doi:10.1056/NEJMoa2511734
5. Dent RA, Cescon DW, Bachelot T, et al. TROPION-Breast02: datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer. Future Oncol. 2023;19(35):2349-2359. doi:10.2217/fon-2023-0228
6. Roche provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer. News release. Roche. August 26, 2021. Accessed March 4, 2026. https://tinyurl.com/36z7fhuf
7. Emens LA, Adams S, Barrios CH, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol. 2021;32(8):983-993. doi:10.1016/j.annonc.2021.05.355
8. Miles D, Gligorov J, André F, et al; IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32(8):994-1004. doi:10.1016/j.annonc.2021.05.801
9. Cardoso F, O'Shaughnessy J, Liu Z, et al. Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2- breast cancer: a randomized phase 3 trial. Nat Med. 2025;31(2):442-448. doi:10.1038/s41591-024-03415-7
10. Schmid P, Zhou X, Dent R. Pembrolizumab in early-stage triple-negative breast cancer. Reply. N Engl J Med. 2025;392(11):1142. doi:10.1056/NEJMc2416491
11. Loi S, Salgado R, Curigliano G, et al. Neoadjuvant nivolumab and chemotherapy in early estrogen receptor-positive breast cancer: a randomized phase 3 trial. Nat Med. 2025;31(2):433-441. doi:10.1038/s41591-024-03414-8
12. Tolaney SM, DeMichele A, Takano T, et al. OptimICE-RD: sacituzumab govitecan + pembrolizumab vs pembrolizumab (± capecitabine) for residual triple-negative breast cancer. Future Oncol. 2024;20(31):2343-2355. doi:10.1080/14796694.2024.2357534
13. Bardia A, Pusztai L, Albain K, et al. TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy. Ther Adv Med Oncol. 2024;16:17588359241248336. Published 2024 Apr 29. doi:10.1177/17588359241248336
14. Schmid P, Oliveira M, O'Shaughnessy J, et al. TROPION-Breast05: a randomized phase III study of Dato-DXd with or without durvalumab versus chemotherapy plus pembrolizumab in patients with PD-L1-high locally recurrent inoperable or metastatic triple-negative breast cancer. Ther Adv Med Oncol. 2025;17:17588359251327992. Published 2025 Apr 17. doi:10.1177/17588359251327992