Combination Immunotherapy Strategies in Breast Cancer
- 98 Downloads
Purpose of Review
We summarize combination immunotherapy strategies for the treatment of breast cancer, with a focus on metastatic disease. First, a general overview of combination approaches is presented according to breast cancer subtype. Second, additional review of promising combination approaches is presented.
Combination strategies utilizing chemotherapy or radiotherapy with immune checkpoint inhibition are being evaluated across multiple phase III trials. Dual immunotherapy strategies, such as dual immune checkpoint inhibition or combined co-stimulation/co-inhibition, have supportive preclinical evidence and are under early clinical investigation. Modulation of the immune microenvironment via cytokines and vaccination strategies, as well as locally focused treatments to enhance antigenic responses, are active areas of research.
Pre-clinical and translational research sheds new light on numerous ways the immune system may be modulated to fight against cancer. We describe current and emerging combination approaches which may improve patient outcomes in metastatic breast cancer.
KeywordsMetastatic breast cancer Combination immunotherapy Treatment
Immunotherapy attracts interest as a therapeutic strategy in breast cancer due to recognition of immune system involvement in the tumor microenvironment, observation that a robust immune response may confer a favorable prognosis, and achievement of meaningful clinical outcomes with immune-based therapies [1, 2••]. Enhanced survival utilizing immunotherapy as monotherapy has been limited, and it is increasingly accepted that in breast cancer, a combination of immunotherapy with other systemic or locally focused treatments may be helpful to induce an immunogenic cell death which promotes and sustains an immune-mediated response [3, 4, 5]. The purpose of this review is to describe combination strategies for immunotherapy in the treatment of breast cancer, with a focus on metastatic disease. First, a general overview of combination approaches across breast cancer subtypes is presented, and second, a more comprehensive review of various combination approaches is reviewed.
Summary of Combination Approaches According to Tumor Subtype
Hormone-Receptor Positive Metastatic Breast Cancer
Selected combination ICI trials in metastatic breast cancer
Phase of study
Chemotherapy plus ICI (TNBC)
Gemcitabine/carboplatin or capecitabine
Nab-paclitaxel or paclitaxel or gemcitabine/carboplatin
Targeted therapies + ICI
Entinostat or ipatasertib or fulvestrant
HR + HER2-
Pertuzumab + trastuzumab
HER2 bi-armed activated T cells
Paclitaxel + trastuzumab + pertuzumab
Olaparib +/- cediranib
RT or capecitabine
Cyclophosphamide + doxorubicin
INCAGN01876 (GITR agonist)
Nivo (phase I), Ipi/nivo (phase II)
NKTR-214, NKTR-262 (TLR agonist)
Entinostat (HDAC inhibitor)
Nivo +/- ipi
BMS-986178 (OX40 agonist)
CDK 4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib are now standard-of-care options for hormone-receptor positive breast cancer, and function primarily by blocking the transition from G1 to S phase of the cell cycle . It has been demonstrated preclinically that CDK4/6 inhibitors may incite anti-tumor immune responses due to interferon production, reduced proliferation of Tregs, and stimulation of effector T lymphocytes which augments the effect of immune checkpoint inhibitors (ICI) [12, 13]. Mouse models have also shown synergistic effects of CDK4/6 and PI3K inhibition with PD-1 and CTLA-4 inhibition . Recently, the combination of abemaciclib plus pembrolizumab (anti-PD-1) was found to be safe in metastatic hormone receptor positive breast cancer, with an ORR of 28.6% at 24 weeks . In comparison, the phase II MONARCH 1 study of abemaciclib monotherapy in HR+/HER2- mBC achieved an ORR of 10.6% with abemaciclib monotherapy at the same 24-week time point and at final 12-month analysis had an ORR of 19.7% . A study assessing the combination of aromatase inhibition with abemaciclib and pembrolizumab has just completed accrual (NCT02779751). Additional trials are in progress evaluating combinations of ICI with small molecule targeted therapies (Table 1).
Because CDK4/6 inhibition may upregulate PD-L1 within the tumor microenvironment, another avenue of investigation in hormone-sensitive breast cancer is to evaluate combination immunotherapy approaches at the time of progression following receipt of CDK4/6 inhibitor. The MORPHEUS trial is a multi-arm study that aims to evaluate second-line hormone–directed therapy (fulvestrant) in combination with immunotherapy (atezolizumab, anti-PD-l/L1) with or without various targeted therapies, including tyrosine kinase inhibitors (e.g., the AKT inhibitor, ipatasertib), angiogenesis inhibitors (e.g., bevacizumab), and epigenetic modifiers (e.g., the histone deacetylase inhibitor, entinostat) (NCT03280563). These therapies are associated with unique immunomodulatory effects. For example, AKT signaling is implicated in macrophage M1/M2 polarization , whereas blockade of vascular endothelial growth factor with bevacizumab may be associated with influx and activation of immune cells into tumors , and entinostat is associated with neutralization of myeloid-derived suppressor cells and enhanced efficacy of anti-PD-1/L1 .
Another potential immunotherapy target in hormone sensitive breast cancer is transforming growth factor beta (TGFβ), a multipotent cytokine which is present at high levels in the tumor microenvironment and is immunosuppressive. TGFβ can directly suppress the effector function of CD4+ and CD8+ T cells by transcriptional regulation of cytotoxic mediators granzyme, perforin, and interferon . In addition, TGFβ limits T cell proliferation and differentiation [21, 22] but may also exclude T cells from the tumor microenvironment by promoting fibrosis and extracellular matrix deposition [23, 24, 25]. TGFβ gene signatures have been found to be enriched among less proliferative luminal-type tumors, raising interest in TGFβ as a potential target for hormone sensitive breast cancer . Furthermore, TGFβ is one of the most abundant factors secreted within bone and is known to stimulate breast cancer bone metastases, which is a common site of metastasis in hormone-sensitive breast cancer . In a mammary carcinoma model, TGFβ blockade at the time of radiation improved radiosensitivity in vitro and in vivo by attenuating DNA damage responses , as well as mediating interferon gamma (IFNγ) production . Addition of anti-PD1 to radiation and TGFβ blockade further improved survival in murine mammary carcinoma models . In light of these data, a number of TGFβ antagonists are being developed in combination with anti-PD-1/L1 in breast cancer. M7824, a bispecific antibody that targets both PD-L1 and TGFβ has demonstrated in murine models an ability to increase CD8+ T cell and NK cell activity, and increase MHC and PD-L1 expression within the tumor . In a small trial, anti-TGFβ (fresolimumab) was evaluated in combination with palliative radiotherapy in metastatic breast cancer. Three of 23 subjects experienced a best response of stable disease; however, in a post hoc analysis, subjects randomized to the higher dose of fresolimumab had a significantly higher median OS (HR 2.73, 95% CI 1.02–7.30, p = .039) .
Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer
HER2 overexpression is found in 15–20% of invasive breast cancers and is associated with aggressive behavior and poor survival related to metastatic recurrence . Targeted anti-HER2 treatments function by inhibiting intracellular signaling, but also by facilitating antibody-dependent cellular cytotoxicity (ADCC), which relies on both the innate and adaptive immune system [33, 34, 35]. Furthermore, anti-HER2 antibodies have been shown to synergize with anti-PD-1/L1 in mammary carcinoma models . A number of trials are evaluating anti-PD-1/L1 with anti-HER2 antibodies +/- chemotherapy. The phase Ib/II PANACEA trial assessed pembrolizumab plus trastuzumab in trastuzumab-resistant advanced HER2+ BC, and showed an overall response rate (ORR) of 15% (90% CI 7–29%) among patients with PD-L1 positive tumors and ORR of 0% in patients with PD-L1 negative tumors . There is an ongoing phase III study evaluating first-line paclitaxel plus trastuzumab plus pertuzumab with or without atezolizumab for metastatic HER2-positive breast cancer (NCT03199885).
Ado-trastuzumab emtansine (T-DM1, Kadcyla) is an antibody-drug conjugate that combines trastuzumab with a potent cytotoxic moiety, emtansine. In preclinical evaluations, T-DM1 potently synergized with ICIs including anti-CTLA-4 and anti-PD-1, resulting in massive T cell infiltration, tumor rejection, Th1 helper T cell polarization, and T regulatory depletion . However, the phase II KATE2 study of trastuzumab-emtansine plus placebo versus atezolizumab in HER-2+ advanced BC failed to demonstrate a clinically significant improvement in PFS (HR 0.82, 95% CI 0.55–1.23, p = .33). Similar to the PANACEA trial, subjects with PD-L1-positive tumors had numerically higher PFS and ORR , indicating that biomarker-driven patient selection may be important for further clinical development of anti-PD-1/anti-HER2 combination approaches in HER2-positive breast cancer.
Additional immunotherapies are being developed to capitalize upon ADCC as a mechanism of tumor cell death. Margetuximab is an anti-HER2 antibody with a genetically enhanced fragment crystallizable (Fc) region that allows for increased FcγRIIIA receptor affinity, which may optimize ADCC-dependent tumor killing by natural killer (NK) cells, particularly in patients with a CD16A low-affinity binding genotype. In a recent phase III trial, margetuximab was associated with modest increases in PFS compared with trastuzumab in HER2+ BC 5.8 mos vs 4.9 mos (HR 0.76, 95% CI 0.59–0.98, p = 0.033), and of comparably greater benefit in patients with a low-affinity CD16A-F allele PFS 6.9 mos vs 5.1 (HR 0.68 95% CI 0.52–0.90, p = 0.005) [40, 41•]. Margetuximab may have unique promise if evaluated in combination with other modulators of ADCC and adaptive immune response. For example, a phase I study of margetuximab plus pembrolizumab is currently in progress (NCT02689284). There are tri-specific antibodies in development that also exhibit enhanced Fc receptor binding in addition to targeting of two surface antigens .
Another unique aspect of HER2-positive metastatic breast cancer is the potential for the HER2 protein to serve as a tumor-associated antigen. Nelipepimut-S, also known as E75, is a 9-amino acid peptide from the extracellular domain of HER2/neu and is capable of eliciting an anti-HER2 immune response. Preclinical data suggested the addition of granulocyte-macrophage colony–stimulating factor (GM-CSF) to nelipepimut (NeuVax) may induce proliferation, maturation, and migration of dendritic cells . Recently, the phase III PRESENT study failed to show benefit of nelipepimut plus GM-CSF for prevention of cancer recurrence in patients with early-stage low-intermediate HER2 positivity . Similarly, a recent phase IIb trial evaluating nelipepimut plus trastuzumab failed to improve disease free survival (DFS) among the intention-to treat (ITT) population (HR 0.62, 95% CI 0.31–1.25, p = 0.18); however, there was a significant benefit in the triple negative breast cancer (TNBC) subgroup (HR = 0.26, p = .013) . Setbacks in clinical development of short peptide–based vaccines has fueled ongoing investigation into different modes of vaccination, including autologous cells, DNA, and dendritic cell (DC)–based vaccines, as well as ongoing evaluation of combinations with various adjuvant therapies.
Triple Negative Metastatic Breast Cancer
Lack of targets and limitations of standard cytotoxic chemotherapy have prompted exploration of combination immunotherapy strategies in TNBC. In a phase III trial (Impassion130), the addition of atezolizumab to chemotherapy (nab-paclitaxel) was demonstrated to improve PFS and lead to a clinically significant improvement in OS among PD-L1-positive unresectable/metastatic TNBCs (PFS 7.5 v 5.0 mo, HR = 0.62; 95% CI, 0.49 to 0.78; p < 0.001), leading to Food and Drug Administration (FDA) approval for this indication [2••]. Interim analysis of the ongoing phase III KEYNOTE-522 trial which evaluates pembrolizumab plus chemotherapy in the neoadjuvant and the adjuvant settings in TNBC demonstrated improvement in the pathological complete response rate regardless of PD-L1 status [46•]. Additionally, there are several ongoing phase III trials evaluating various chemotherapy backbones combined with anti-PD1/L1 (Table 1). Other emerging targets for combination therapy in TNBC include poly(ADP-Ribose) polymerase 1 (PARP) inhibitors, tyrosine kinase inhibitors, immune co-stimulatory/co-inhibitory antibodies, androgen receptor antagonists, and epigenetic modulators . For more in-depth reading, see article by Kim (this issue).
Deficiencies in homologous recombination correlate with improved response to platinum-based chemotherapy and PARP inhibitors [48, 49, 50, 51], particularly in breast cancers with germline/somatic mutations in the BRCA1/2 gene . There is emerging interest in combination ICI with PARP inhibitors . Preclinical data suggests that PARP inhibition upregulates PD-L1 expression in breast cancer cell lines and animal models. Furthermore, blockade of cytotoxic T lymphocyte antigen 4 (CTLA-4)—a T cell co-inhibitory molecule—was shown to be effective in combination with PARP inhibitors in an ovarian cancer BRCA-deficient model [53, 54]. A phase I/II trial of niraparib with pembrolizumab in advanced TNBC has achieved an ORR of 28% and disease control rate (CR/PR or SD ≥ 16 weeks) in evaluable patients of 80% . Several ongoing trials are evaluating PARP inhibition plus ICI (NCT03167619, NCT 03801369, NCT02484404, NCT03330405) in breast cancer.
Emerging Combination Immunotherapy Approaches
Next-generation immune modulator pathways classified by cell type and action
Adenosine signaling pathway
Combination with Initiators of Immunogenic Cell Death
Immunogenic cell death is a form of cell death sufficient to induce an adaptive immune response through molecular signaling . Damage-associated molecular pattern (DAMP) signaling activates DCs via toll-like receptors (TLRs) and results in initiation of tumor-specific B cell and T cells adaptive responses . Standard approaches for the treatment of breast cancer, including radiotherapy (RT) and chemotherapy, have the ability to induce immunogenic cell death. In a melanoma model, anti-CTLA4 with RT was associated with PD-L1 upregulation, and the addition of anti-PD-L1 reversed T cell exhaustion, promoted clonal T cell expansion within the tumor, and enhanced response . Numerous current trials are ongoing to determine optimal dosing and schedule of RT for immunogenic purposes. Cytotoxic chemotherapy has immune-modulatory effects such as expanding or activating NK cells, DC cells, and T cells; depleting tumor-associated macrophages, myeloid derived suppressor cells, T-regs, and IFNγ and PD-L1 upregulation [60, 61, 62, 63]. Since the FDA approval of atezolizumab with nab-paclitaxel, this has become a robust area of research, with several phase III trials assessing utility of dual chemotherapy with ICI (Table 1).
Selected vaccine/oncolytic combination trials in metastatic breast cancer
Phase of study
Oncolytic virus–based vaccine
Paclitaxel or endocrine therapy
Dendritic cell–based vaccine
Tumor blood vessel antigen
Tumor cell–based vaccine
SV-BR-1-GM (GM-CSF secreting line)
PVX-410 (XBP1, CD138, CS1)
HER2 intracellular domain
Polysaccharide-K + pertuzumab or trastuzumab
Personalized synthetic long peptide
Nab-paclitaxel + durvalumab
LTX-315 (oncolytic peptide)
Ipilimumab or pembrolizumab
Globo H carbohydrate antigen
To date, the majority of clinically investigated ICIs target T cells, yet there are additional cell types that may facilitate anti-tumor immunity, each with targetable co-inhibitory molecules. For example, CD47 is expressed on tumor cells and interacts with signal regulatory protein alpha on macrophages to trigger a “don’t eat me” signal . CD47 is an innate immune checkpoint whose overexpression correlates with poor prognosis . Targeting the CD47 protein may be relevant in combination with anti-HER2 antibody therapy or other antibody-based therapies, as blockade of CD47 may enhance antibody-mediated phagocytosis of tumor cells via ADCC. In a phase I study, an anti-CD47 molecule (ALX148) was safely combined with trastuzumab, and was associated with an ORR of 22% among trastuzumab-resistant gastric cancers . Although CD47 signaling involves innate immune cells, murine models also suggest that CD47 blockade improves CD8+ T cell response [75, 76]. ALX148 was also safely combined with pembrolizumab (anti PD-1), with encouraging activity in non-small cell lung cancer and head/neck squamous cell cancer cohorts .
A number of antibody-drug conjugates are being developed in breast cancer, such as trastuzumab-deruxtecan (DS-8201a) which is a novel drug-antibody combination which pairs anti-HER targeting with a topoisomerase-inhibitor. There are two ongoing phase Ib trials assessing DS-8201a in combination with ICI in mBC: one with pembrolizumab (NCT04042701) and one with nivolumab (NCT03523572). Sacituzumab govitecan combines Trop-2 targeting with a topoisomerase-inhibitor and was shown to be active in pretreated TNBC, with an ORR of 33.3% (95% CI 24.6–43.1) and median duration of response 7.7 months (95% CI 4.9–10.8) . There are no reported preclinical or clinical trials evaluating the combination of sacituzumab with ICIs or other immunotherapies in breast cancer; however, this is an active area of interest.
Bispecific dual immunomodulators combining two inhibitory functions are being explored . Ongoing is a phase 1 trial of XmAb20717, a combined PD-1 x CTLA-4 antibody in selected advanced solid tumors (NCT03517488). Its safety data will be reviewed with interest as combinations of anti-PD-1/L1 plus anti-CTLA-4 are known to be more toxic than monotherapy. LAG-3 is a surface molecule which binds to major histocompatibility complex II (MHCII) on antigen presenting cells, and may serve to block T cells from binding MHCII and becoming activated.  A number of antibodies against LAG-3 are in development, as well as bispecific antibodies that engage both LAG-3 and PD-1/L1. (NCT03219268, NCT03440437).
Co-stimulation and Co-inhibition Combination Approaches
There exist numerous co-stimulatory targets including the tumor necrosis factor receptor (TNFR) family members OX40, 4-1BB, and GITR [81, 82, 83, 84]. OX40 is expressed on CD4+ and CD8+ T cells and when ligated, has the ability expand T cells, improve T cell effector function, improve T cell memory, and facilitate tumor clearance . In mammary carcinoma models, anti-OX40 plus anti-PD-L1 was more effective than monotherapy in inducing regression [86, 87], and was associated with increases in tumor-specific T cells.  In an independent study, anti-OX40 plus anti-CTLA-4 plus HER2 vaccine seemed to reverse T cell anergy, enhance CD8+ T cell effector function, and increase longevity of memory T cell response . A bispecific antibody targeting CTLA-4 and OX40 (ATOR-1015) has demonstrated efficacy in tumor models and is being tested in a phase 1 trial (NCT03782467) . Timing of PD1/L1 blockade may be crucial for the efficacy of combination therapy. For example, in mammary carcinoma models, sequential administration of OX-40 followed by anti-PD1 was more effective than monotherapy, whereas concurrent blockade was not effective [90, 91], and was associated with high levels of peripheral cytokine production. Anti-OX40 has also been combined with radiation in a phase I trial (NCT01862900) which provided stereotactic body RT to metastatic lesions in the liver or lung with aOX40-mAb in metastatic breast cancer . These targets may be more effective when combined with modulators of innate immunity, such as with ligands of the DNA-sensing stimulator of interferon genes (STING) pathway . STING protein is expressed in multiple cell types including macrophages, T cells, DCs, and can trigger an anti-cancer immune response . In a mouse model, STING signaling improved tumor clearance in combination with anti PD-1 and anti-OX40 .
Tumor Microenvironment Modulation
Cytokines may exhibit inhibitory or stimulating effects and, therefore, can be therapeutically targeted [95, 96]. One example TGFβ, a multipotent cytokine which is described above in the context of hormone-sensitive breast cancer. Other cytokines being evaluated with anti-PD-l/L1 in breast cancer include intratumoral IL-12 and pegylated IL-2. IL-12 is a potent inflammatory cytokine that induces IFNγ production and Th1 T cell response, but is too toxic for systemic administration. In a mouse model, intratumoral IL-12 was associated with improved antitumor responses when delivered in combination with anti-PD-1 . A pilot study has been conducted in metastatic TNBC whereby intratumoral IL-12 plasmid was safely administered by electroporation, and was associated with increases in TIL count by immunohistochemistry (from mean 3 to 11% by day 28 of treatment, vs 5% in untreated tumors by day 28) . A phase II study combining intratumoral plasmid IL-12 with pembrolizumab is in progress .
IL-2 is a central factor for orchestrating an anti-tumor immune response, and is associated with activation and proliferation of both CD8+ and CD4+ T cells. Systemic administration is FDA-approved for the treatment of metastatic melanoma and renal cell carcinoma (RCC); however, the therapy is toxic with a narrow therapeutic window and requires inpatient administration. The pegylated IL-2 prodrug, NKTR-214, is associated with prolonged half-life and favorable pharmacokinetics, enabling outpatient administration and reduced toxicity. NKTR-214 was effective in combination with ICI in both melanoma and mammary carcinoma models . In a phase I study, NKTR-214 was shown to be well-tolerated relative to systemic IL-2 in a phase I study (grade III adverse event rate of 18%), with preliminary signals of clinical activity in melanoma/RCC . The combination of NKTR-214 and nivolumab is currently being assessed in phase I and II studies in breast cancer (NCT02983045, NCT03435640).
Antigenic Cell Death: Radiation Therapy and Cryoablation
The abscopal effect, whereby the immune system creates a robust response against distant metastases following local treatment, powerfully illustrates the concept of immune-mediated cell death . Radiotherapy and cryotherapy are well-established locally focused anti-cancer treatments which are being combined with immunotherapy in attempt to enhance known immunogenic effects against cancer . The combinations of RT with immunotherapy and cryoablation with immunotherapy face hurdles to development such as establishing effective dosing, the optimal number of treatments, timing of intervention, and optimal immunotherapeutic combination agent.
There are numerous clinical trials investigating RT with ICI for treatment of breast cancer. In the mTNBC setting, a single-arm phase II study assessing the combination of RT with pembrolizumab demonstrated a partial response of 33% in 9 of 17 patients eligible at 13 weeks, 11% with stable disease in patients unselected for PD-L1 expression . In contrast, a single-arm phase II study in HR+/HER2- mBC evaluated RT with pembrolizumab in the palliative setting and did not demonstrate a clinical benefit, though reported no unexpected adverse events . Ongoing are several other studies including a pilot trial investigating the combination of preoperative pembrolizumab and RT boost prior to standard of care surgery and adjuvant RT (NCT03366844). In metastatic breast cancer, a combination of brain radiation with tremelimumab and durvalumab is being assessed in a pilot phase for patients with mBC with intracranial involvement (NCT02563925), and a phase II study is currently evaluating the efficacy of pembrolizumab with RT in mTNBC and high-risk hormone-positive disease (NCT02730130).
The possible permutations of RT with existing immunotherapies are vast, and combinations of RT with PARP inhibition, OX-40 signaling, TGF-β inhibition, and vaccines among others which will be discussed in a separate review in more detail (this issue).
Several existing trials of cryotherapy in combination with immunotherapy in local non-metastatic cancers offer implications for future treatment of metastatic disease. A pilot study utilizing cryoablation with ipilimumab demonstrated safety in women with operable breast cancer . A phase II randomized study of perioperative ipilimumab, nivolumab, and cryoablation versus standard care in resectable TNBC following standard of care neoadjuvant therapy is ongoing . The number of cryoablative treatments and timing for optimal outcome needs to be established; in one retrospective observational study of patients with metastatic breast cancer, multiple cryoablations were associated with greater median OS compared with single cryoablations (76 months vs 48 months, p = 0.0005) .
Antigen Delivery and Antigenic Cell Death: Vaccines and Oncolytic Viruses
Vaccines may be in the form of peptides, carbohydrates, organelles, and cells. They have the potential to enact powerful effector functions, or alter the tumor microenvironment to support an immune response. Critical to the success of vaccines is the proper selection of antigen, vector, adjuvant, route, dose, and schedule . Combinations of vaccines with radiotherapy and chemotherapy are ongoing areas of research and covered in more detail in accompanying reviews (this issue). In addition to HER2-directed vaccines, another promising target is the mannose receptor, as shown in a phase II study of oxidized mannan-MUC1 which demonstrated encouraging reductions in recurrence rate (12.5% versus 60%) in a small study . The multivalent poxviral–based cancer vaccine, PANVAC, which targets CEA and MUC1 and also contains genes for costimulatory molecules B7.1, ICAM-1, and LFA-3, showed a numerically increased PFS of 7.9 months vs 3.9 months when combined with docetaxel (HR 0.65, 95% CI 0.34–1.14, p = 0.09) .
Cell-based vaccines can induce broad activation of the immune system, and decreased resistance of tumor cells. SV-BR-1-GM (GVAX) is composed of tumor cells transfected with the GM-CSF gene. These cells over-express genes encoding tumor-associated antigens, and express MHC II and other immunostimulatory proteins which facilitate a coordinated anti-tumor response . In a phase I study, GVAX was associated with regression of distant metastases [111, 112]. GVAX is currently in phase II trials (NCT03328026) in combination with pembrolizumab.
Proteasome inhibition thus poses an attractive target by which to enhance the accumulation of misfolded protein, which triggers an unfolded protein response and leads to cell cycle arrest and apoptosis, an approach that is promising in breast cancer models [113, 114, 115]. A phase II trial of 12 patients did not show any benefit against mTNBC as monotherapy . However, a small study demonstrated a trend of improved PFS in hormone-sensitive breast cancer when combined with fulvestrant (PFS 5.4 v. 9.0 months, HR 0.73, 95% CI 0.49–1.09 p = 0.06) . Inhibition of the proteasome can also been explored as a method of generating vaccines against intracellular proteins that are otherwise sequestered from antigen presentation via the autophagy process . An ongoing study is evaluating an autophagy-based vaccine in combination with anti-PD-1 and anti-OX40 in metastatic TNBC (NCT02737475).
Oncolytic viruses have been approved for use in melanoma. Talimogene laherparepvec (T-VEC) is an HSV-1 virus modified to replicate in tumor cells and express GM-CSF to increase tumor-antigen presentation by dendritic cells. T-VEC is currently being evaluated in breast cancer in combination with anti-CTLA4, chemotherapy, or endocrine therapy (Table 3). CVA21 (CAVATAK) is a coxsackie-based oncolytic virus which adheres to ICAM-1 in order to enter a cell, then eventually lyses the cell releasing more viruses which can perpetuate cell lysis . In mammary carcinoma models, CAVATAK in combination with doxorubicin resulted in synergistic cell death . A non-viral oncolytic strategy utilizing the peptide LTX-315 is studied in a phase I trial in combination with ipilimumab or pembrolizumab (NCT01986426).
Combination immunotherapy strategies are intriguing as they may generate a more complete and durable response against tumors. However, at this point, the field is dominated by preclinical data and phase I evaluations. The sheer number of possible combination approaches is daunting and presents a unique challenge for the future of drug development. Novel adaptive clinical trial designs will hopefully enable more efficient screening of these combination approaches, as well as the development of next-generation biomarkers that will allow us to personalize combination immunotherapy according to the biological characteristics of a patient’s tumor and pre-existing immune response.
Compliance with Ethical Standards
Conflict of Interest
David Page reports personal fees from Genentech; grants and personal fees from Merck; personal fees from Novartis; personal fees from Puma; personal fees from Nanostring; personal fees from Nektar; personal fees from Syndax; grants and personal fees from Brooklyn Immunotherapeutics; and grants and personal fees from Bristol Myers-Squibb outside the submitted work. Heather McArthur has consulted for Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, and TapImmune. Dr. McArthur also has research supported by Bristol-Myers Squibb, MedImmune, LLC/AstraZenica, and Merck. Brie Chun declares no conflicts of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Nagarajan D, McArdle SEB. Immune landscape of breast cancers. Biomedicines. 2018;6(1). https://doi.org/10.3390/biomedicines6010020.
- 2.•• Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–21. https://doi.org/10.1056/NEJMoa1809615This randomized controlled phase III trial evaluated atezolizumab plus nab-paclitaxel against placebo plus nab-paclitaxel in the treatment of untreated mTNBC. The combination of atezolizumab and nab-paclitaxel achieved prolonged PFS in the intention-to-treat group and in a PD-L1 positive subgroup. CrossRefPubMedGoogle Scholar
- 3.Sanchez K, Page D, McArthur HL. Immunotherapy in breast cancer: an overview of modern checkpoint blockade strategies and vaccines. Curr Probl Cancer. 2016;40(2-4):151–62. https://doi.org/10.1016/j.currproblcancer.2016.09.009.CrossRefPubMedGoogle Scholar
- 15.Tolaney SM, Kabos P, Dickler MN, Gianni L, Jansen V, Lu Y, et al. Updated efficacy, safety, & PD-L1 status of patients with HR+, HER2- metastatic breast cancer administered abemaciclib plus pembrolizumab. J Clin Oncol. 2018;36(15_suppl):1059. https://doi.org/10.1200/JCO.2018.36.15_suppl.1059.CrossRefGoogle Scholar
- 16.Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, et al. MONARCH 1, A phase II study of abemaciclib, a CDK4 and CDK6 Inhibitor, as a single agent, in patients with refractory HR(+)/HER2(-) metastatic breast cancer. Clin Cancer Res. 2017;23(17):5218–24. https://doi.org/10.1158/1078-0432.CCR-17-0754.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Orillion A, Hashimoto A, Damayanti N, Shen L, Adelaiye-Ogala R, Arisa S, et al. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res. 2017;23(17):5187–201. https://doi.org/10.1158/1078-0432.CCR-17-0741.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Garrison K, Hahn T, Lee WC, Ling LE, Weinberg AD, Akporiaye ET. The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis. Cancer Immunol Immunother. 2012;61(4):511–21. https://doi.org/10.1007/s00262-011-1119-y.CrossRefPubMedGoogle Scholar
- 28.Bouquet F, Pal A, Pilones KA, Demaria S, Hann B, Akhurst RJ, et al. TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res. 2011;17(21):6754–65. https://doi.org/10.1158/1078-0432.CCR-11-0544.CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Stagg J, Loi S, Divisekera U, Ngiow SF, Duret H, Yagita H, et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci U S A. 2011;108(17):7142–7. https://doi.org/10.1073/pnas.1016569108.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 2019;20(3):371–82. https://doi.org/10.1016/S1470-2045(18)30812-X.CrossRefPubMedGoogle Scholar
- 39.Emens L, Esteva F, Beresford M, Saura C, De Laurentiis M, Kim S-B, et al. Abstract PD3-01: results from KATE2, a randomized phase 2 study of atezolizumab (atezo) + trastuzumab emtansine (T-DM1) vs placebo (pbo) + T-DM1 in previously treated HER2+ advanced breast cancer (BC). Cancer Res. 2019;79(4 Supplement):PD3-01-PD3. https://doi.org/10.1158/1538-7445.sabcs18-pd3-01.CrossRefGoogle Scholar
- 40.Nordstrom JL, Muth J, Erskine CL, Sanders C, Yusko EC, Emerson RO, et al., editors. High frequency of HER2-specific immunity observed in patients (pts) with HER2+ cancers treated with margetuximab (M), an Fc-enhanced anti-HER2 monoclonal antibody (mAb). Chicago: American Society of Clinical Oncology Annual Meeting; 2019.Google Scholar
- 41.• Rugo HS, Im S-A, Wright GLS, Escriva-de-Romani S, DeLaurentiis M, Cortes J, et al. SOPHIA primary analysis: a phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37(15_suppl):1000. https://doi.org/10.1200/JCO.2019.37.15_suppl.1000This randomized controlled phase III trial assessed a novel HER-2 targeted antibody with enhanced Fc binding affinity at CD16A-FcyRIIIA receptor, and demonstrated improved PFS in a subgroup with low-affinity CD16A alleles. CrossRefGoogle Scholar
- 44.Clifton GT, Peace KM, Holmes JP, Vreeland TJ, Hale DF, Herbert GS, et al. Initial safety analysis of a randomized phase II trial of nelipepimut-S + GM-CSF and trastuzumab compared to trastuzumab alone to prevent recurrence in breast cancer patients with HER2 low-expressing tumors. Clin Immunol. 2019;201:48–54. https://doi.org/10.1016/j.clim.2019.02.011.CrossRefPubMedGoogle Scholar
- 45.Hickerson A, Clifton GT, Hale DF, Peace KM, Holmes JP, Vreeland TJ, et al. Final analysis of nelipepimut-S plus GM-CSF with trastuzumab versus trastuzumab alone to prevent recurrences in high-risk, HER2 low-expressing breast cancer: a prospective, randomized, blinded, multicenter phase IIb trial. J Clin Oncol. 2019;37(8_suppl):1. https://doi.org/10.1200/JCO.2019.37.8_suppl.1.CrossRefGoogle Scholar
- 46.• Eisele P, Mulhearn C. Merck’s KEYTRUDA ® (pembrolizumab) in combination with chemotherapy met primary endpoint of pathological complete response (pCR) in pivotal phase 3 KEYNOTE-522 trial in patients with triple-negative breast cancer (TNBC). Business Wire; 2019. This press release announces interim data from the ongoing phase III KEYNOTE-522 trial evaluating combination pembrolizumab and chemotherapy in neoadjuvant and adjuvant TNBC suggests improved pathological CR rate, final analyses upcoming.Google Scholar
- 48.Kaklamani VG, Jeruss JS, Hughes E, Siziopikou K, Timms KM, Gutin A, et al. Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579). Breast Cancer Res Treat. 2015;151(3):629–38. https://doi.org/10.1007/s10549-015-3435-y.CrossRefPubMedGoogle Scholar
- 49.Richardson AL, Silver DP, Szallasi Z, Birkbak NJ, Wang ZC, Iglehart JD, et al. Abstract P3-06-11: Homologous recombination deficiency (HRD) assay predicts response to cisplatin neoadjuvant chemotherapy in patients with triple negative breast cancer. Cancer Res. 2015;75(9 Supplement):P3-06-11-P3-06-11. https://doi.org/10.1158/1538-7445.sabcs14-p3-06-11.CrossRefGoogle Scholar
- 50.Sharma P, Barlow WE, Godwin AK, Pathak H, Isakova K, Williams D, et al. Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with adjuvant doxorubicin and cyclophosphamide (SWOG S9313). Ann Oncol. 2018;29(3):654–60. https://doi.org/10.1093/annonc/mdx821.CrossRefPubMedGoogle Scholar
- 54.Higuchi T, Flies DB, Marjon NA, Mantia-Smaldone G, Ronner L, Gimotty PA, et al. CTLA-4 Blockade Synergizes Therapeutically with PARP inhibition in BRCA1-deficient ovarian cancer. Cancer Immunol Res. 2015;3(11):1257–68. https://doi.org/10.1158/2326-6066.CIR-15-0044.CrossRefPubMedPubMedCentralGoogle Scholar
- 55.Vinayak S, Tolaney S, Schwartzberg L, Mita M, McCann G, Tan A, et al. Abstract PD5-02: Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162). Cancer Res. 2019;79(4 Supplement):PD5-02-PD5. https://doi.org/10.1158/1538-7445.sabcs18-pd5-02.CrossRefGoogle Scholar
- 56.• Mazzarella L, Duso BA, Trapani D, Belli C, D'Amico P, Ferraro E, et al. The evolving landscape of 'next-generation' immune checkpoint inhibitors: a review. Eur J Cancer. 2019;117:14–31. https://doi.org/10.1016/j.ejca.2019.04.035This systematic review describes the rationale for emerging checkpoint inhibitors which target signaling pathways of interest in an antitumor immune response. CrossRefPubMedGoogle Scholar
- 62.Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, et al. Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res. 2015;75(23):5034–45. https://doi.org/10.1158/0008-5472.CAN-14-3098.CrossRefPubMedGoogle Scholar
- 66.Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17(11):1558–68. https://doi.org/10.1016/S1470-2045(16)30366-7.CrossRefPubMedPubMedCentralGoogle Scholar
- 67.•• Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–92. https://doi.org/10.1016/S1470-2045(18)30700-9This randomized controlled trial of dual ICI with ipilimumab and nivolumab versus nivolumab or ipilimumab alone in the treatment of advanced melanoma demonstrated a durable survival benefit 4 years follow up with dual ICI and with nivolumab alone. CrossRefPubMedGoogle Scholar
- 68.Hammers HJ, Plimack ER, Infante JR, Rini BI, McDermott DF, Lewis LD, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol. 2017;35(34):3851–8. https://doi.org/10.1200/JCO.2016.72.1985.CrossRefPubMedGoogle Scholar
- 70.• Schadendorf D, Wolchok JD, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807–14. https://doi.org/10.1200/JCO.2017.73.2289This retrospective analysis of pooled phase II and III trials of combination nivolumab and ipilimumab found similar median PFS and ORR between groups of patients who discontinued dual ICI during the induction phase and those who did not. CrossRefPubMedPubMedCentralGoogle Scholar
- 71.Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017;18(1):31–41. https://doi.org/10.1016/S1470-2045(16)30624-6.CrossRefPubMedGoogle Scholar
- 74.Chow LQM, Gainor JF, Lakhani NJ, Chung HC, Lee K-W, Lee J, et al. A phase I study of ALX148, a CD47 blocker, in combination with established anticancer antibodies in patients with advanced malignancy. J Clin Oncol. 2019;37(15_suppl):2514. https://doi.org/10.1200/JCO.2019.37.15_suppl.2514.CrossRefGoogle Scholar
- 75.Soto-Pantoja DR, Terabe M, Ghosh A, Ridnour LA, DeGraff WG, Wink DA, et al. CD47 in the tumor microenvironment limits cooperation between antitumor T cell immunity and radiotherapy. Cancer Res. 2014;74(23):6771–83. https://doi.org/10.1158/0008-5472.CAN-14-0037-T.CrossRefPubMedPubMedCentralGoogle Scholar
- 77.Chow LQM, Gainor JF, Lakhani NJ, Chung HC, Lee K-W, Lee J, et al. editors. A phase I study of ALX148, a CD47 blocker, in combination with established anticancer antibodies in patients with advanced malignancy. ASCO 2019 meeting, Chicago; 2019, IL: J Clin OncolGoogle Scholar
- 86.Polesso F, Weinberg AD, Moran AE. Late stage tumor regression after PD-L1 blockade with a concurrent OX40 agonist. 2018.Google Scholar
- 88.Linch SN, Kasiewicz MJ, McNamara MJ, Hilgart-Martiszus IF, Farhad M, Redmond WL. Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T cell anergy and promotes survival in tumor-bearing mice. Proc Natl Acad Sci U S A. 2016;113(3):E319–27. https://doi.org/10.1073/pnas.1510518113.CrossRefPubMedPubMedCentralGoogle Scholar
- 89.Kvarnhammar AM, Veitonmäki N, Hägerbrand K, Dahlman A, Smith KE, Fritzell S, et al. The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation. J Immunother Cancer. 2019;7(1):103. https://doi.org/10.1186/s40425-019-0570-8.CrossRefPubMedPubMedCentralGoogle Scholar
- 91.Shrimali RK, Ahmad S, Verma V, Zeng P, Ananth S, Gaur P, et al. Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T cell apoptosis. Cancer Immunol Res. 2017;5(9):755–66. https://doi.org/10.1158/2326-6066.CIR-17-0292.CrossRefPubMedPubMedCentralGoogle Scholar
- 92.Crittenden M, Conlin AK, Moxon N, Curti BD. Phase I/II study of stereotactic body radiation therapy (SBRT) to metastatic lesions in the liver or lung in combination with monoclonal antibody to OX40 in patients with progressive metastatic breast cancer (mBC) after systemic therapy. J Clin Oncol. 2015;33(15_suppl):TPS3103-TPS. https://doi.org/10.1200/jco.2015.33.15_suppl.tps3103.CrossRefGoogle Scholar
- 93.Foote JB, Kok M, Leatherman JM, Armstrong TD, Marcinkowski BC, Ojalvo LS, et al. A STING agonist given with OX40 receptor and PD-L1 modulators primes immunity and reduces tumor growth in tolerized mice. Cancer Immunol Res. 2017;5(6):468–79. https://doi.org/10.1158/2326-6066.CIR-16-0284.CrossRefPubMedPubMedCentralGoogle Scholar
- 98.Telli ML, Zablotsky K, Gargosky SE, Twitty CG, Wapnir IL. Abstract CT022: intratumoral plasmid IL-12 and electroporation in pre-treated inoperable locally advanced or recurrent triple-negative breast cancer (TNBC). Cancer Res. 2018;78(13 Supplement):CT022-CT. https://doi.org/10.1158/1538-7445.am2018-ct022.CrossRefGoogle Scholar
- 99.Telli M, Wapnir I, Vinayak S, Chang J, Alemany C, Twitty C, et al. Abstract OT2-06-03: a phase 2 study of intratumoral tavokinogene telseplasmid (tavo) plus electroporation with pembrolizumab in patients with inoperable locally advanced or metastatic triple negative breast cancer. Cancer Res. 2019;79(4 Supplement):OT2-06-3-OT2--3. https://doi.org/10.1158/1538-7445.sabcs18-ot2-06-03.CrossRefGoogle Scholar
- 100.Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res. 2016;22(3):680–90. https://doi.org/10.1158/1078-0432.ccr-15-1631.CrossRefPubMedGoogle Scholar
- 101.Bentebibel S-E, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9(6):711–21. https://doi.org/10.1158/2159-8290.cd-18-1495.CrossRefPubMedGoogle Scholar
- 104.McArthur HL, Barker CA, Gucalp A, Lebron-Zapata L, Wen YH, Kallman C, et al. A phase II, single arm study assessing the efficacy of pembrolizumab (Pembro) plus radiotherapy (RT) in metastatic triple negative breast cancer (mTNBC). J Clin Oncol. 2018;36(15_suppl):1017. https://doi.org/10.1200/JCO.2018.36.15_suppl.1017.CrossRefGoogle Scholar
- 105.Barroso-Sousa R, Krop I, Trippa L, Tan-Wasielewski Z, Li T, Osmani W et al., editors. A Phase II study of pembrolizumab in combination with palliative radiotherapy (RT) for hormone receptor-positive (HR+) metastatic breast cancer (MBC). 2019 ASCO annual meeting; 2019 June 2, Chicago, IL; 2019. J Clin Oncol.Google Scholar
- 106.McArthur HL, Diab A, Page DB, Yuan J, Solomon SB, Sacchini V, et al. A pilot study of preoperative single-dose ipilimumab and/or cryoablation in women with early-stage breast cancer with comprehensive immune profiling. Clin Cancer Res. 2016;22(23):5729–37. https://doi.org/10.1158/1078-0432.CCR-16-0190.CrossRefPubMedPubMedCentralGoogle Scholar
- 107.McArthur H, Comen E, Solomon S, Rodine M, DiLauro AC, Leal J, et al. Abstract OT2-06-05: A randomized phase II study of peri-operative ipilimumab, nivolumab and cryoablation versus standard peri-operative care in women with residual triple negative early stage/resectable breast cancer after standard-of-care neoadjuvant chemotherapy. Cancer Res. 2019;79(4 Supplement):OT2-06-5-OT2--5. https://doi.org/10.1158/1538-7445.sabcs18-ot2-06-05.CrossRefGoogle Scholar
- 109.Vassilaros S, Tsibanis A, Pietersz GA, McKenzie IF, Apostolopoulos V. Up to 15-year clinical follow-up of a pilot phase III immunotherapy study in stage II breast cancer patients using oxidized mannan-MUC1. Immunotherapy. 2013;5(11):1177–82. https://doi.org/10.2217/imt.13.126.CrossRefPubMedGoogle Scholar
- 110.Heery CR, Ibrahim NK, Arlen PM, Mohebtash M, Murray JL, Koenig K, et al. Docetaxel alone or in combination with a therapeutic cancer vaccine (PANVAC) in patients with metastatic breast cancer: a randomized clinical trialdocetaxel alone vs with PANVAC for metastatic breast cancerdocetaxel alone vs with PANVAC for metastatic breast cancer. JAMA Oncol. 2015;1(8):1087–95. https://doi.org/10.1001/jamaoncol.2015.2736.CrossRefPubMedPubMedCentralGoogle Scholar
- 111.Lacher MD, Bauer G, Fury B, Graeve S, Fledderman EL, Petrie TD, et al. SV-BR-1-GM, a clinically effective GM-CSF-secreting breast cancer cell line, expresses an immune signature and directly activates CD4(+) T lymphocytes. Front Immunol. 2018;9:776. https://doi.org/10.3389/fimmu.2018.00776.CrossRefPubMedPubMedCentralGoogle Scholar
- 113.Weyburne ES, Wilkins OM, Sha Z, Williams DA, Pletnev AA, de Bruin G, et al. Inhibition of the proteasome β2 site sensitizes triple-negative breast cancer cells to β5 inhibitors and suppresses Nrf1 activation. Cell Chem Biol. 2017;24(2):218–30. https://doi.org/10.1016/j.chembiol.2016.12.016.CrossRefPubMedPubMedCentralGoogle Scholar
- 114.Jones MD, Liu JC, Barthel TK, Hussain S, Lovria E, Cheng D, et al. A proteasome inhibitor, bortezomib, inhibits breast cancer growth and reduces osteolysis by downregulating metastatic genes. Clin Cancer Res. 2010;16(20):4978–89. https://doi.org/10.1158/1078-0432.CCR-09-3293.CrossRefPubMedPubMedCentralGoogle Scholar
- 115.Meißner T, Mark A, Williams C, Berdel WE, Wiebe S, Kerkhoff A, et al. Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events. Cold Spring Harb Mol Case Stud. 3(4):a001677. https://doi.org/10.1101/mcs.a001677.CrossRefGoogle Scholar
- 116.Yang CH, Gonzalez-Angulo AM, Reuben JM, Booser DJ, Pusztai L, Krishnamurthy S, et al. Bortezomib (VELCADE®) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Ann Oncol. 2006;17(5):813–7. https://doi.org/10.1093/annonc/mdj131.CrossRefPubMedGoogle Scholar
- 117.Adelson K, Ramaswamy B, Sparano JA, Christos PJ, Wright JJ, Raptis G, et al. Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: a New York Cancer Consortium trial. Npj Breast Cancer. 2016;2:16037. https://doi.org/10.1038/npjbcancer.2016.37.CrossRefPubMedPubMedCentralGoogle Scholar
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.