Treatment with checkpoint inhibitors has shown durable responses in a number of solid tumors, including melanoma, lung, and renal cell carcinoma. However, most breast cancers are resistant to ...monotherapy with checkpoint inhibitors. Radiation therapy (RT) has been shown to have a number of immunostimulatory effects, including priming the immune system, recruiting immune cells to the tumor environment, and altering the immunosuppressive effects of the tumor microenvironment. RT therefore represents a promising adjuvant therapy to checkpoint blockade in breast cancer.
We review the data from the checkpoint blockade studies on breast cancer reported to date, the mechanisms by which RT potentiates immune responses, the preclinical and clinical data of checkpoint blockade and RT combinations, and the landscape of current clinical trials of RT and immune checkpoint inhibitor combinations in breast cancer.
Clinical trials with checkpoint blockade therapy have demonstrated response rates of up to 19% in breast cancer, and many of the responses are durable. Preclinical data indicate that RT combined with checkpoint inhibition synergizes not only to enhance antitumor efficacy but also to induce responses outside of the radiation field. Thus multiple clinical trials are currently investigating the combination of checkpoint inhibition with RT.
The use of combination strategies that incorporate chemotherapy and/or local strategies such as RT may be needed to augment responses to immune therapy in breast cancer. Preclinical and clinical results show that RT in combination with checkpoint blockade may be a promising therapeutic option in breast cancer.
Background
The current study was conducted to evaluate the efficacy and safety of pembrolizumab‐mediated programmed cell death protein 1 inhibition plus radiotherapy (RT) in patients with metastatic ...triple‐negative breast cancer who were unselected for programmed death‐ligand 1 expression.
Methods
The current study was a single‐arm, Simon 2‐stage, phase 2 clinical trial that enrolled a total of 17 patients with a median age of 52 years (range, 37‐73 years). An RT dose of 3000 centigrays (cGy) was delivered in 5 daily fractions. Pembrolizumab was administered intravenously at a dose of 200 mg within 3 days of the first RT fraction, and then every 3 weeks ± 3 days until disease progression. The median follow‐up was 34.5 weeks (range, 2.1‐108.3 weeks). The primary endpoint of the current study was the overall response rate (ORR) at week 13 in patients with unirradiated lesions measured using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Secondary endpoints included safety and progression‐free survival. Exploratory objectives were to identify biomarkers predictive of ORR and progression‐free survival.
Results
The ORR for the entire cohort was 17.6% (3 of 17 patients; 95% CI, 4.7%‐44.2%), with 3 complete responses (CRs), 1 case of stable disease, and 13 cases of progressive disease. Eight patients died prior to week 13 due to disease progression. Among the 9 women assessed using RECIST version 1.1 at week 13, 3 (33%) achieved a CR, with a 100% reduction in tumor volume outside of the irradiated portal. The CRs were durable for 18 weeks, 20 weeks, and 108 weeks, respectively. The most common grade 1 to 2 toxicity (assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) was dermatitis (29%). Four grade 3 adverse events were attributed to pembrolizumab: fatigue, lymphopenia, and infection. No were no grade 4 adverse events or treatment‐related deaths reported.
Conclusions
The combination of pembrolizumab and RT was found to be safe and demonstrated encouraging activity in patients with poor‐prognosis, metastatic, triple‐negative breast cancer who were unselected for programmed death‐ligand 1 expression. Larger clinical trials of checkpoint blockade plus RT with predictive biomarkers of response are needed.
The current phase 2, multi‐institutional study evaluates whether the combination of the programmed cell death protein 1 immune checkpoint inhibitor pembrolizumab and radiotherapy (RT) is safe and effective in patients with metastatic triple‐negative breast cancer (mTNBC). Among 17 women in the current study with pretreated mTNBC who received pembrolizumab and RT, the combination appears safe and demonstrates an encouraging signal within a poor‐prognosis population, indicating that further study of the combination is warranted.
Opinion Statement
Immunotherapy has become one of the greatest advances in medical oncology over the last century; however, the optimal application for the treatment of breast cancer remains an ...active area of investigation. Modern immunotherapy strategies augment the immune system and ideally, permit durable tumor-specific immune memory. In fact, several monoclonal antibodies that mediate the immune checkpoint receptors have provided the most clinically meaningful improvement for breast cancer patients to date, particularly for the triple negative subtype. Checkpoint blockade as monotherapy has demonstrated some encouraging results, although some combination strategies appear to augment those responses and may be particularly effective when administered earlier in the course of disease. For example, the combination of atezolizumab and nab-paclitaxel as first-line therapy for metastatic triple negative breast cancer demonstrated significant improvements in progression-free survival when compared with chemotherapy alone. Herein, we review the data for immune therapy in breast cancer and highlight promising future directions.
Background
Loss of HER2 “positivity” can occur in patients with residual disease after neoadjuvant treatment, but the incidence of HER2‐positivity loss after neoadjuvant dual HER2‐targeted treatment ...plus chemotherapy, the current standard‐of‐care for most early stage HER2‐positive breast cancers, is not well described. Previous studies that report the HER2 discordance rate after neoadjuvant treatment also do not include the novel HER2‐low category. In this retrospective study, we determine the incidence and prognostic impact of HER2‐positivity loss, including the evolution to HER2‐low disease, after neoadjuvant dual HER2‐targeted therapy with chemotherapy.
Methods
Clinicopathologic data for patients with stage I‐III HER2+ breast cancer diagnosed between 2015 and 2019 were reviewed in this single institution retrospective study. Patients who received dual HER2‐targeted treatment with chemotherapy were included, and HER2 status before and after neoadjuvant therapy was interrogated.
Results
A total of 163 female patients were included in the analysis with a median age of 50 years. A pathologic complete response (pCR as defined by ypT0/is) was achieved in 102 (62.5%) of 163 evaluable patients. Among the 61 patients with residual disease after neoadjuvant therapy, 36 (59.0%) had HER2‐positive and 25 (41.0%) had HER2‐negative residual disease. Of the 25 patients with HER2‐negative residual disease, 22 (88%) of patients were classified as HER2‐low. After a median follow‐up of 3.3 years, patients who retained HER2‐positivity after neoadjuvant treatment had a 3‐year IDFS rate of 91% (95% CI, 91%–100%), while patients who lost HER2‐positivity had a 3‐year IDFS rate of 82% (95% CI, 67%–100%).
Conclusion
Almost half of patients with residual disease following neoadjuvant dual HER2‐targeted therapy plus chemotherapy lost HER2‐positivity. The loss of HER2‐positivity may not confer negative prognostic impact, although the results were limited by short follow‐up time. Further research on the HER2 status after neoadjuvant treatment may help guide treatment decisions in the adjuvant setting.
The incidence of loss of HER2‐positivity after neoadjuvant dual HER2‐targeted therapy with chemotherapy is not well described, but may affect adjuvant systemic therapy recommendations. In this study, almost half of the patients with residual disease after neoadjuvant dual HER2‐targeted treatment plus chemotherapy lost HER2‐positivity at the time of surgery. Of these patients, almost all were classified as HER2‐low. The loss of HER2‐positivity may not confer negative prognostic impact, although the results were limited by short follow‐up time.
Purpose
Immune checkpoint inhibition (ICI) has demonstrated clinically significant efficacy when combined with chemotherapy in triple negative breast cancer (TNBC). Although many patients derived ...benefit, others do not respond to immunotherapy, therefore relying upon innovative combinations to enhance response. Local therapies such as radiation therapy (RT) and cryotherapy are immunogenic and potentially optimize responses to immunotherapy. Strategies combining these therapies and ICI are actively under investigation. This review will describe the rationale for combining ICI with targeted local therapies in breast cancer.
Methods
A literature search was performed to identify pre-clinical and clinical studies assessing ICI combined with RT or cryotherapy published as of August 2021 using PubMed and ClinicalTrials.gov.
Results
Published studies of ICI with RT and IPI have demonstrated safety and signals of early efficacy.
Conclusion
RT and cryotherapy are local therapies that can be integrated safely with ICI and has shown promise in early trials. Randomized phase II studies testing both of these approaches, such as P-RAD (NCT04443348) and ipilimumab/nivolumab/cryoablation for TNBC (NCT03546686) are current enrolling. The results of these studies are paramount as they will provide long term data on the safety and efficacy of these regimens.
Purpose
The aim of this study was to compare fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and contrast-enhanced computed tomography (CE-CT) for the prediction of ...progression-free survival (PFS) and disease-specific survival (DSS) in patients with stage IV breast cancer undergoing systemic therapy.
Methods
Sixty-five patients with metastatic breast cancer treated with first- or second-line systemic therapy in prospective clinical trials were included. Response to treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for CE-CT and by PET Response Criteria in Solid Tumors (PERCIST), respectively.
Results
All responders by RECIST (
n
= 22) were also responders by PERCIST, but 40% (17/43) of non-responders by RECIST were responders by PERCIST. Responses according to RECIST and PERCIST both correlated with PFS, but PERCIST showed a significantly higher predictive accuracy (concordance index for PFS: 0.70 vs. 0.60). One-year PFS for responders vs. non-responders by RECIST was 59% vs. 27%, compared to 63% vs. 0% by PERCIST. Four-year DSS of responders and non-responders by RECIST was 50% and 38%, respectively (
p
= 0.2, concordance index: 0.55) as compared to 58% vs. 18% for PERCIST (
p
< 0.001, concordance index: 0.65). Response on PET/CT was also a significantly better predictor for DSS than disease control on CE-CT.
Conclusions
In patients with metastatic breast cancer, tumor response on PET/CT appears to be a superior predictor of PFS and DSS than response on CE-CT. Monitoring tumor response by PET/CT may increase the power of clinical trials using tumor response as an endpoint, and may improve patient management in clinical routine.
Breast irradiation has long been utilized in the adjuvant or metastatic setting to eliminate microscopic disease or to palliate existing disease, respectively. However, preclinical data have ...demonstrated that radiation can also alter the tumor microenvironment and induce antitumor immune responses. As a result, multiple clinical studies have been undertaken and have reported synergy between radiation and immune checkpoint blockade across various cancer types. Given recent clinical successes with immune checkpoint blockade in both early-stage and metastatic breast cancer, there has been substantial interest in combining radiation and immunotherapy to enhance local and systemic immune responses. Herein, we review the preclinical rationale for combining radiotherapy and immunotherapy, the early clinical trials that have adopted this strategy in breast cancer, and the landscape of ongoing relevant clinical trials. Finally, we propose future directions based on promising preclinical studies that integrate radiation, checkpoint blockade, and novel agents for the treatment of breast cancer.
The abscopal effect refers to the ability of localized radiation to trigger systemic antitumor effects. Over the past 50 years, reports on the abscopal effect arising from conventional radiation have ...been relatively rare. However, with the continued development and use of immunotherapy strategies incorporating radiotherapy with targeted immunomodulators and immune checkpoint blockade, the abscopal effect is becoming increasingly relevant in less immunogenic tumors such as breast cancer. Here, we review the mechanism of the abscopal effect, the current preclinical and clinical data, and the application of the abscopal effect in designing clinical trials of immunotherapy combined with radiotherapy in breast cancer.
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