September 2015, Vol. 2, No. 5
Immunotherapy for Breast Cancer, the Most Commonly Diagnosed Cancer Among Women Worldwide
Excluding cancers of the skin, breast cancer is the most frequently diagnosed cancer in women.1 An estimated 234,190 new cases of invasive breast cancer (231,840 in women and 2350 in men) are expected to be diagnosed among Americans during 2015.1 Breast cancer ranks second as a cause of cancer death in women (after lung cancer); an estimated 40,730 breast cancer deaths (40,290 among women, 440 among men) are expected in 2015.1
When diagnosed early, breast cancer treatment generally involves surgery, which, depending on the stage and molecular characteristics of the cancer, may be followed by chemotherapy, radiation therapy, or targeted therapy (including hormone therapy).2
In approximately 1 in 5 breast cancers, the protein HER2 is overexpressed.3 Cancers overexpressing HER2 may be treated with targeted therapies such as trastuzumab,4 lapatinib,5 pertuzumab,6 or ado-trastuzumab emtansine7 (Table 1).
In the pivotal study that established that trastuzumab was highly effective when added to standard chemotherapy in the frontline treatment of women with HER2-positive metastatic breast cancer, benefit appeared to accrue in those patients whose tumors expressed the HER2 oncoprotein at the 3+ level by immunohistochemistry (IHC) or those patients whose tumors demonstrated evidence of HER2 gene amplification by fluorescence in situ hybridization (FISH) testing.8 Similarly, when trastuzumab was used as monotherapy in women with metastatic breast cancer that had progressed following cytotoxic chemotherapy, 3+ overexpression of HER2, but not 2+ expression, was associated with response to treatment.8,9 These and other studies have led to the recommendation that trastuzumab should be administered to patients with breast cancer whose tumors exhibit 3+ overexpression or gene amplification. Thus, although treatment with trastuzumab and other HER2-directed therapies is associated with significant efficacy, only patients with the highest levels of HER2 expression have the potential to respond.8 Moreover, many patients expressing high levels of HER2 progress or relapse despite receiving the best HER2-directed treatments and thus require novel treatment approaches.8
Approximately 2 of 3 breast cancers are hormone receptor positive—they contain receptors for the hormones estrogen (ER-positive cancers) and/or progesterone (PR-positive cancers).3 Tamoxifen, an agent that blocks estrogen in breast cancer cells, is often used in women with hormone receptor–positive invasive breast cancer.3,10 Other agents that block estrogen in breast cancer include toremifene11 and fulvestrant.12
Aromatase inhibitors, which block an enzyme (aromatase) responsible for making small amounts of estrogen in postmenopausal women, is also used in women with hormone receptor–positive breast cancer.3
Breast tumors that fail to express ER, PR, and HER2 (known as triple-negative breast cancer) have a poor prognosis and are typically treated with traditional cytotoxic chemotherapy, as no targeted therapy options are currently available.13 For patients with ER-positive or PR-positive breast cancer who are refractory to endocrine therapy, targeted therapeutic options remain quite limited. New therapeutic strategies are needed to improve clinical outcomes for patients with breast cancer, particularly those with advanced disease.
Immunotherapeutic Approaches for Breast Cancer
A phase 2 trial of glembatumumab vedotin (CDX-011), an antibody-drug conjugate, is under way in patients with advanced triple-negative breast cancer whose cancer cells make a protein called glycoprotein NMB, to which glembatumumab vedotin binds (NCT01997333).14
A phase 2 study of margetuximab (MGAH22), an anti-HER2 monoclonal antibody, is under way in patients with relapsed or refractory advanced breast cancer whose tumors express HER2 at the 2+ level by IHC and lack HER2 gene amplification by FISH (NCT01828021). This study will evaluate whether treatment of patients with tumors that would not be expected to respond to trastuzumab therapy, namely those that lack HER2 gene amplification and express the oncoprotein at the 2+ level by IHC, may benefit from treatment with margetuximab. The study investigators calculate that if 5 or more responses are seen in 41 evaluable patients, then further clinical development of the antibody will be justified.15
Research has shown that 20% of all triple-negative breast tumors express the programmed death-1 (PD-1) ligand 1 (PD-L1).16 It is thought that PD-L1 expression may hinder antitumor T-cell responses.13
As part of a phase 1a study (NCT01375842), MPDL3280A, a PD-L1–targeted immunotherapy, was evaluated in 54 patients with both PD-L1–positive and PD-L1–negative metastatic triple-negative breast cancer.13 These patients had a median age of 48 years (range, 29-82 years), 52% had an ECOG performance status (ECOG PS) of 0, and 44% had an ECOG PS of 1. At baseline, visceral metastases were present in 59% of patients, and bone metastases were present in 11% of patients. Eighty-five percent of patients had received ≥4 prior systemic regimens (neoadjuvant, adjuvant, or metastatic), including anthracyclines (78%), taxanes (82%), and platinum agents (15% cisplatin, 41% carboplatin). Of the 54 patients who could be assessed for adverse events (AEs), 63% experienced ≥1 treatment-related AEs, with 11% experiencing ≥1 grade 3 AEs; 1 patient experienced a grade 4 event. The most common treatment-related AEs were fatigue, fever, nausea, and loss of appetite.
Among 21 efficacy-evaluable patients with PD-L1 IHC 2 or 3 (13 IHC 2 and 8 IHC 3), the overall response rate was 19%, and 3 of 4 responses are ongoing. Patients with evidence of durable nonclassical responses suggestive of pseudoprogression were also observed. Overall, the 6-month progression-free survival rate was 27%. Biomarker analysis revealed transient elevation of plasma cytokines and proliferating CD8 cells following MPDL3280A treatment. The authors concluded that MPDL3280A was generally well tolerated and demonstrated promising efficacy in pretreated patients with metastatic PD-L1 IHC 2 or 3 triple-negative breast cancer. Furthermore, circulating biomarker analyses revealed pharmacodynamic responses to MPDL3280A.
Currently, MPDL3280A is under investigation in a phase 3 study in combination with a nanoparticle albumin-bound formulation of paclitaxel (nab-paclitaxel) compared with placebo with nab-paclitaxel for patients with previously untreated metastatic triple-negative breast cancer (Table 2).17
Pembrolizumab, a monoclonal antibody directed against the PD-1 receptor on the cell surface, was approved by the FDA in 2014 for the treatment of patients with advanced or unresectable melanoma following progression on prior therapies. The drug blocks the PD-1 receptor, preventing binding and activation of its 2 ligands, PD-L1 and PD-L2, causing the activation of T-cell–mediated immune responses against tumor cells. In the phase 1b KEYNOTE-012 study (NCT01848834), women with metastatic triple-negative breast cancer expressing PD-L1 received pembrolizumab until disease progression or intolerable toxicity.18,19 An ECOG PS of 0 or 1, no systemic steroid therapy, and no active brain metastases were required for enrollment. Of the 32 evaluable patients with PD-L1–positive tumors (mean age, 52 years), 46.9% had received ≥3 prior lines of therapy for metastatic disease. Among the 27 patients evaluable for response by RECIST, the confirmed overall response rate was 18.5%, including 1 complete response and 4 partial responses. As of November 10, 2014, median follow-up duration was 9.9 months. Median time to response was 18 weeks (range, 7-32 weeks). Median duration of response was not reached (range, 15-40+ weeks), with 3 of 5 responders on treatment for ≥11 months. The 6-month progression-free survival rate was 23.3%. Treatment-related AEs occurred in 56.3% of patients and were of grade 3 to 5 severity in 15.6%. One case of treatment-related disseminated intravascular coagulation led to death. The authors concluded that pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity, including durable responses, in women with heavily pretreated, PD-L1–positive metastatic triple-negative breast cancer. Pembrolizumab is currently being evaluated in a phase 2 study (Table 2).20
Ibrutinib is a targeted therapy, specifically a Bruton’s tyrosine kinase inhibitor, that is approved by the FDA for the treatment of patients with mantle cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia with 17p deletion, and Waldenström’s macroglobulinemia.21 The combination of ibrutinib and MEDI4736, an anti–PD-L1 checkpoint inhibitor, is being investigated in a phase 1b/2 study (NCT02403271) in patients with relapsed or refractory solid tumors, including breast cancer.22
Indoleamine 2,3-dioxygenase (IDO) is one of several immune checkpoints involved in tumor immune escape. The IDO enzyme, activated in dendritic cells and macrophages, helps create an environment that favors suppression and tolerance.23 In a phase 1 study, indoximod (1-methyl-D-tryptophan), an IDO pathway inhibitor, was active in combination with the chemotherapeutic agent docetaxel in patients with metastatic solid tumors.24 A phase 2 study of a taxane chemotherapy (docetaxel or paclitaxel) in combination with indoximod is under way in metastatic breast cancer (NCT01792050).25
Therapeutic Cancer Vaccines
For patients with breast cancer, the most advanced vaccine is nelipepimut-S (formerly known as E75). The formulation is a human leukocyte antigen (HLA)-A2/A3–restricted immunogenic peptide derived from the HER2 protein, combined with the immunoadjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) to make a vaccine designed for the prevention of clinical recurrences in patients with high-risk, disease-free breast cancer.26 The nelipepimut-S vaccine was investigated in the adjuvant setting to prevent disease recurrence in a phase 1/2 study of patients with node-positive or high-risk node-negative tumors that expressed any degree of HER2.27 HLA-A2/3–positive patients were vaccinated; others were followed prospectively as controls. Of 195 enrolled patients, 187 were evaluable: 108 (57.8%) in the vaccinated group and 79 (42.2%) in the control group. The 5-year disease-free survival rate was 89.7% for the vaccine group compared with 80.2% for the control group (P = .08; Figure). Because of the trial design, 65% of patients received less than the optimal vaccine dose. The 5-year disease-free survival rate was 94.6% in optimally dosed patients and 87.1% in suboptimally dosed patients (Figure). A voluntary booster program was initiated, and among the 21 patients who were optimally boosted, there was only 1 recurrence (ie, the disease-free survival rate was 95.2%). Currently, a phase 3 study (PRESENT) is investigating the nelipepimut-S vaccine plus GM-CSF versus GM-CSF alone in patients with early-stage node-positive breast cancer whose tumors express low or intermediate levels of the HER2 protein (HER2 1+ by IHC or HER2 2+ by IHC/FISH) (Table 3).28 To be eligible for the study, patients must have had a primary tumor stage T1 to T3 at initial diagnosis that was completely excised or been receiving neoadjuvant therapy before surgery, and must not have received prior trastuzumab therapy. The vaccine is also being evaluated in 2 phase 2 studies in combination with trastuzumab in other patient populations (Table 3).29,30
E39 is a peptide vaccine derived from folate binding protein, which is expressed on the surface of most breast and ovarian cancer cells. J65 is an attenuated version of E39.31 A prospective, randomized, nonblinded, single center phase 1b study is under way at MD Anderson Cancer Center in which patients with breast or ovarian cancer receive E39 and J65 on various dosing schedules. Patients included in the study have a diagnosis of breast or ovarian cancer, have completed their standard courses of therapy, and are disease free (NCT02019524).32
GM-CSF–secreting tumor vaccines are bioactive, but they are limited by disease burden and immune tolerance.33 It was demonstrated in a single-arm feasibility study (N = 20) that the addition of cyclophosphamide and the HER2-specific monoclonal antibody trastuzumab enhanced vaccine activity. This combination immunotherapy was safe, with clinical benefit (ie, complete response plus partial response plus stable disease) rates at 6 months and 1 year of 55% (95% CI, 32%-77%; P = .013) and 40% (95% CI, 19%-64%), respectively. Median progression-free survival and overall survival durations were 7 months (95% CI, 4-16) and 42 months (95% CI, 22-70), respectively. The study authors concluded that further investigation of cyclophosphamide-modulated vaccination with trastuzumab is warranted. Therefore, a randomized, phase 2, open-label study (NCT00971737) is comparing the combination of cyclophosphamide and an allogeneic GM-CSF–secreting breast tumor vaccine with the combination of cyclophosphamide plus vaccine plus trastuzumab for the treatment of patients with metastatic breast cancer that does not overexpress HER2 (Table 3).34
Historically, breast cancer has not been perceived as an immunogenic tumor when compared with other cancers such as melanoma and renal cell carcinoma, which have long used immunotherapy such as interleukin-2 with some success.35 However, interest in breast cancer immunotherapy is rising due to recent reports of objective responses in metastatic triple-negative breast cancer with both pembrolizumab and MPDL3280A. In general, the greatest benefit of breast cancer vaccines appears to be in the minimally residual disease state settings in patients who have not been heavily pretreated. Strategies that combine established breast cancer therapies, including targeted therapies and chemotherapy, with immune checkpoint blockade, breast cancer vaccines, or both, are likely to achieve additive or synergistic clinical activity.36
- American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 3.2015. www.nccn.org/professionals/physician_gls/f_guidelines.asp#breast. Accessed August 15, 2015.
- American Cancer Society. Breast Cancer. www.cancer.org/cancer/breastcancer/detailedguide/index. Accessed August 13, 2015.
- Herceptin [package insert]. South San Francisco, CA: Genentech, Inc; 2015.
- Tykerb [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2015.
- Perjeta [package insert]. South San Francisco, CA: Genentech, Inc; 2015.
- Kadcyla [package insert]. South San Francisco, CA: Genentech, Inc; 2015.
- McKeage K, Perry CM. Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs. 2002;62:209-243.
- Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:719-726.
- Nolvadex [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2004.
- Fareston [package insert]. Bridgewater, NJ: ProStrakan Inc; 2012.
- Faslodex [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2012.
- Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Presented at: American Association for Cancer Research Annual Meeting 2015: April 18-22, 2015; Philadelphia, PA. Abstract 2859.
- Study of glembatumumab vedotin (CDX-011) in patients with metastatic, gpNMB over-expressing, triple negative breast cancer (METRIC). https://clinicaltrials.gov/ct2/show/NCT01997333. Accessed August 15, 2015.
- Phase 2 study of the monoclonal antibody MGAH22 (margetuximab) in patients with relapsed or refractory advanced breast cancer. https://clinicaltrials.gov/ct2/show/NCT01828021. Accessed August 15, 2015.
- Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2:361-370.
- A study of MPDL3280A in combination with nab-paclitaxel compared with placebo with nab-paclitaxel for patients with previously untreated metastatic triple negative breast cancer. https://clinicaltrials.gov/ct2/show/NCT02425891. Accessed August 15, 2015.
- Nanda R, Chow LQ, Dees EC, et al. A phase 1b study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S1-09.
- Buisseret L, Specht J, Dees EC, et al. KEYNOTE-012: a phase Ib study of pembrolizumab (MK-3475) in patients (pts) with metastatic triple-negative breast cancer (mTNBC). Presented at: IMPAKT Breast Cancer Conference; May 7-9, 2015; Brussels, Belgium. Abstract 14P.
- Study of pembrolizumab (MK-3475) monotherapy for metastatic triple-negative breast cancer (MK-3475-086/KEYNOTE-086). https://clinicaltrials.gov/ct2/show/NCT02447003. Accessed August 15, 2015.
- Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics, Inc; 2015.
- A multi-center study of ibrutinib in combination with MEDI4736 in subjects with relapsed or refractory solid tumors. https://clinicaltrials.gov/ct2/show/NCT02403271. Accessed August 15, 2015.
- Sheridan C. IDO inhibitors move center stage in immuno-oncology. Nat Biotechnol. 2015;33:321-322.
- Soliman HH, Jackson E, Neuger T, et al. A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors. Oncotarget. 2014;5:8136-8146.
- Study of chemotherapy in combination with IDO inhibitor in metastatic breast cancer. https://clinicaltrials.gov/ct2/show/NCT01792050. Accessed August 2015.
- Schneble EJ, Berry JS, Trappey FA, et al. The HER2 peptide nelipepimut-S (E75) vaccine (NeuVaxTM) in breast cancer patients at risk for recurrence: correlation of immunologic data with clinical response. Immunotherapy. 2014;6:519-531.
- Mittendorf EA, Clifton GT, Holmes JP, et al. Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients. Ann Oncol. 2014;25:1735-1742.
- Efficacy and safety study of NeuVaxTM (nelipepimut-S or E75) vaccine to prevent breast cancer recurrence (PRESENT). www.clinicaltrials.gov/ct2/show/NCT01479244. Accessed August 15, 2015.
- Combination immunotherapy with Herceptin and the HER2 vaccine NeuVax. https://clinicaltrials.gov/ct2/show/NCT01570036. Accessed August 15, 2015.
- Phase II trial of combination immunotherapy with NeuVax and trastuzumab in high-risk HER2+ breast cancer patients (HER3+). https://clinicaltrials.gov/ct2/show/NCT02297698. Accessed August 16, 2015.
- Tutt B. Immunotherapy trials offer hope to patients with high-risk or metastatic breast cancer. MD Anderson Cancer Center. www.mdanderson.org/publications/oncolog/previous-issues/2015-july/immunotherapy-trials-offer-hope-to-patients-with-high-risk-or-metastatic-breast-cancer.html. Accessed August 4, 2015.
- Phase Ib trial of two folate binding protein peptide vaccines (E39 and J65) in breast and ovarian cancer patients. https://clinicaltrials.gov/ct2/show/NCT02019524. Accessed August 16, 2015.
- Chen G, Gupta R, Petrik S, et al. A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer. Cancer Immunol Res. 2014;2:949-961.
- Cyclophosphamide and vaccine therapy with or without trastuzumab in treating patients with metastatic breast cancer. https://clinicaltrials.gov/ct2/show/ NCT00971737. Accessed August 16, 2015.
- Soliman H. Immunotherapy strategies in the treatment of breast cancer. Cancer Control. 2013;20:17-21.
- Emens LA, Middleton G. The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer Immunol Res. 2015;3:436-443.
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