Cancer Immunotherapy

Breast Cancer

Breast cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development. This page features information on breast cancer and immunotherapy clinical trials for breast cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to people with breast cancer.

Breast cancer is the most commonly diagnosed cancer among women worldwide. Each year, breast cancer represents 11 percent of all cancers diagnosed globally, and it is the second leading cause of cancer-related death among women. In 2008, there were 1.38 million new diagnoses worldwide and 458,000 deaths. Approximately 1 in 8 U.S. women will develop invasive breast cancer at some point in their lives; for men, the lifetime risk is about 1 in 1,000.

Prognosis and Risk Factors: The overall 5-year survival rate for breast cancer is now 90%—a dramatic improvement over the early 1960s when the rate was 63%. When considered by stage, the 5-year survival rates are 99% for localized disease and 84% for regionally advanced disease that may have spread to neighboring lymph nodes. For patients with stage IV disease with distant metastases, the 5-year survival rate drops to 23%.

Increased risk for breast cancer is associated with a personal or family history of the disease and inherited genetic mutations in the breast cancer susceptibility genes BRCA1 and BRCA2. These mutations account for approximately 5%-10% of all breast cancer cases, but are rare in the general population (less than 1%). Women with BRCA1 and BRCA2 mutations have an estimated 40% to 85% lifetime risk of developing breast cancer. Other known risk factors include obesity, use of MHT (a hormone therapy that combines progestin and estrogen), high breast tissue density, alcohol consumption, and physical inactivity.

Treatment: 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, such as tamoxifen or the aromatase inhibitors letrozole, anastrozole, or exemestane).

Cancers over-expressing HER2 (HER2 3+ or FISH positive) may be treated with targeted therapies such as trastuzumab (Herceptin™) and, in the case of advanced cancer, lapatinib (Tykerb™), pertuzumab (Perjeta™), or TDM-1 (Kadcyla™). Of these the newest treatment options are pertuzumab and TDM-1. Pertuzumab (Perjeta™) was approved by the FDA in 2012 for first-line treatment of HER2+ metastatic breast cancer in combination with trastuzumab (Herceptin™) and the chemotherapy docetaxel (Taxotere®). In a phase III trial, the addition of pertuzumab resulted in an improvement in progression-free survival of approximately 6 months (18.5 months in the pertuzumab group versus 12.4 months in the control group).


Setting the stage for combining trastuzumab and pertuzumab, in 2005, Yosef Yarden, Ph.D., a 1987 CRI Postdoctoral Fellow, first demonstrated in the laboratory that combining trastuzumab with an antibody directed against a different part of HER2 is more effective than trastuzumab alone against HER2+ breast cancer [1].



TDM-1 (Kadcyla™) is a HER2-targeted antibody with chemotherapy (a microtubule inhibitor) attached by a linker, and is designed to deliver chemotherapy directly to the tumor via HER-2. TDM-1 was approved by the FDA in 2013 for patients with HER-2-positive, metastatic breast cancer who have previously received trastuzumab or one of the taxane chemotherapies (paclitaxel (Taxol™) or docetaxel (Taxotere™). In a Phase III trial that compared treatment with lapatinib (Tykerb™) and the chemotherapy drug capecitabline (Xeloda™) to treatment with TDM-1, TDM-1 improved progression-free survival by 3.2 months (9.6 months in the TDM-1 group versus 6.4 months in the control group) and overall survival by 5.8 months (30.9 months in the TDM-1 group compared to 25.1 months in the control arm).

Although treatment with trastuzumab has shown efficacy, particularly in combination with chemotherapy, only patients with the highest levels of HER-2 expression, representing approximately 20% of breast cancer patients, are eligible for trastuzumab and other HER-2-targeted therapies. Moreover, studies with Trastuzumab therapy show that many patients progress despite treatment or relapse, requiring novel approaches to increase anti-HER-2 antibody efficacy and to induce more sustained immune responses against HER-2.

In patients who do not express HER2, or who express it at lower levels (HER2 1+ or 2+ or FISH negative), targeted therapeutic options remain limited, and new strategies specific for alternative breast cancer markers and pathways will be required to improve treatment outcomes for breast cancer patients.

Because current treatments are unlikely to cure advanced breast cancer, patients in otherwise good health are encouraged to think about taking part in clinical trials of other promising treatments. Go to our Clinical Trial Finder to find clinical trials of immunotherapies for breast cancer that are currently enrolling patients.

 

Immunotherapy for Breast Cancer

Although breast cancer has historically not been considered a favorable target for immunotherapies, several preclinical and clinical studies have provided important insights and clinical data that support its potential to improve clinical outcomes for patients with breast cancer. Overall, immunotherapy holds several key advantages over conventional chemotherapeutic treatments, as well as over new targeted therapies. Not only does immunotherapy generally confer fewer side effects, enabling it to be administered for longer periods of time and/or in combination with other agents without added toxicity, but patients may also be less likely to develop resistance to immunotherapeutic approaches because of the immune system’s ability to target multiple cancer antigens and pathways simultaneously, and to offer longer-term protection due to its capacity for memory.

Some immunotherapies that have shown promise in recent clinical trials include:

  • NeuVax (nelipepimut-S or E75) is under investigation to prevent breast cancer recurrence among patients with low to intermediate levels of HER2 expression (HER2 1+ and 2+) following surgery. A phase III trial (PRESENT) was announced in January 2012 and is currently enrolling patients (NCT01479244). The trial has been granted a Special Protocol Assessment (SPA) by the FDA, meaning that, if the trial meets its pre-specified endpoint, it will fulfill the necessary criteria to file for regulatory approval.
  • A vaccine targeting the AE37 peptide is also undergoing testing in a phase II trial involving 600 women who have completed all primary standard treatment and are without clinical evidence of disease (NCT00524277). Interim results from the trial, presented at the 2012 meeting of the American Society of Clinical Oncology (ASCO), demonstrated that the treatment could delay cancer recurrence, with increased benefit seen in women with low levels of HER2 expression (HER2 1+ or 2+).
  • GVAX, a therapeutic vaccine made from breast cancer cell lines irradiated and engineered to express the immune molecule GM-CSF, is being tested in a phase II trial in patients with stage IV breast cancer that does not overexpress HER-2 (NCT00971737).
  • Based on preclinical and an early-phase study in multiple cancer types, an activating anti-OX40 antibody is being tested in a phase I/II trial for patients with stage IV breast cancer who have failed prior hormone or chemotherapy (NCT01642290). OX40 is a costimulatory molecule expressed after T cell activation that enhances T cell survival and anti-cancer effector function.

Go to our Clinical Trial Finder to be matched with clinical trials of immunotherapies for breast cancer that are currently enrolling patients.

 

CRI Impact: Historical Contributions to Breast Cancer Research

The Cancer Research Institute’s commitment to breast cancer goes back nearly four decades, when CRI began funding the New York Metropolitan Breast Cancer group, an alliance of physicians and surgeons from 18 medical institutions committed to developing a coordinated breast cancer diagnosis and treatment program.

Some of CRI’s historic contributions to the immunological understanding and treatment of breast cancer include:

  • In 1975, Dr. Fanny Lacour, at the Institut Gustav-Roussy in Paris, France, first reported that the use of polyadenylic-polyuridylic acid (Poly-AU) in combination with surgery increased breast cancer survival rates in mice. Poly-AU is a synthetic form of double-stranded RNA that enhances immune response by mimicking viral infection. Although it is no longer used, the synthetic double-stranded RNA known as Poly-ICLC is being tested as an adjuvant in several CRI-funded vaccine trials to determine its effect in boosting the anti-cancer immune response.
  • In 1983, Dr. Maurice Black, at New York Medical College in Valhalla, NY, reported that patients who demonstrate postoperative immunity to their breast cancer tissue are more likely to remain free of disease than patients lacking immune reactions. This study provided one of the first signs that breast cancer was subject to immunosurveillance and therefore could potentially benefit from approaches designed to induce or enhance anti-breast cancer immune responses.
  • Mien-Chie Hung, Ph.D., a CRI Fellow from 1983 to 1986, was one of the first three to clone the HER2/neu oncogene [2], a key milestone enabling the development of trasuzumab for HER2+ breast cancer. Since then, he has made several additional major discoveries, including showing that CXCR4, a receptor for immune signaling molecules called chemokines, plays a major role in breast cancer metastasis to the lungs, liver, and bone in HER2+ cancers. Dr. Hung is currently the vice president for basic research and director of the Breast Cancer Research Program at The University of Texas MD Anderson Cancer Center in Houston, TX.

 

CRI Breast Cancer Research Today

Today, several CRI investigators are undertaking studies with implications for breast cancer immunotherapy. Their projects and discoveries include:

  • Danila Valmori, Ph.D., and Maha Ayyoub, Ph.D., members of the CRI/Ludwig Cancer Vaccine Collaborative at the Centre de Lutte Contre le Cancer Nantes-Atlantique, in Nantes, France, conducted a systematic survey of naturally occurring immune responses against the NY-ESO-1 antigen in patients with primary breast cancer. Their studies revealed that NY-ESO-1 antibodies can identify a subgroup of hormone receptor-negative breast cancer patients with frequent expression of NY-ESO-1 who may be candidates for immunotherapy. Based on these results, Drs. Valmori and Ayyoub are planning to initiate a vaccine trial in patients with estrogen receptor-negative breast cancer.
  • Haihui Lu, Ph.D., a CRI Fellow at the Whitehead Institute for Biomedical Research, has identified a surface marker that distinguishes a population of breast cancer cells that are more prone to metastasis and demonstrate higher levels of ‘stemness,’ the ability to seed other tumors. She plans to test whether or not molecules designed to target the marker can block the signaling necessary for maintaining the cells’ stem-like properties, which could lead to new antibody-based immunotherapies for breast cancer.
  • A CRI Fellow at the University of Washington School of Medicine in Seattle, John T. Wilson, Ph.D., is working to enhance T cell responses against tumors by using “smart” polymers to create a new type of cancer vaccine and to test this new strategy in a preclinical model of human breast cancer. Dr. Wilson hopes that these studies will translate into a clinically viable class of vaccines for the treatment and prevention of breast and other cancers.
  • Ming Li, Ph.D., a CLIP grantee at Memorial Sloan-Kettering Cancer Center in New York, New York, are studying an immunosuppressive pathway that is activated in tumor-associated immune cells in breast cancer models. This pathway is also the target of beta blockers, which are used to treat high blood pressure and which have been associated with increased survival among breast cancer patients. In his project, Dr. Li is investigating whether beta blockers target T cells to control breast tumor development, and is also working to understand how this pathway regulates T cell responses to tumors, which may reveal novel targets for the immunotherapy of breast cancer.
  • Robert D. Schreiber, Ph.D., an associate director of CRI’s Scientific Advisory Council based at Washington University School of Medicine in Saint Louis, Missouri, developed a new model of breast cancer that more closely resembles the progression of hormone receptor-positive disease in humans, overcoming a major obstacle in the study of breast cancer and the development of new immune-based therapies for the disease. His CRI-funded studies have enabled him to define many of the developmental stages of breast cancer and have established several important characteristics of tumors at different stages in their development. These studies have opened up new avenues for therapeutic intervention throughout the different stages, and have also aided in the identification of biomarkers that can help in determining disease diagnosis and prognosis.
  • Paola Betancur, Ph.D., a 2012-2015 CRI Postdoctoral Fellow, and Diane Tseng , 2012-2014 STaRT Graduate Student, both at Stanford University School of Medicine, are working to validate and test therapeutic strategies targeting the CD47 protein to treat cancer. CD47 provides a “don’t eat me” signal to macrophages, a type of white blood cell that engulfs and digests dead and harmful cells. This may be a key way that cancer avoids immune attack. Studies have shown that treatment with an anti-CD47 antibody can shrink tumors drastically in models of numerous cancers, including breast cancer. Paola Betancur and Diane Tseng are working to understand the fundamental biologic mechanisms of anti-CD47 therapy and how to improve it for patients.

 

Sources: National Cancer Institute; National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2012; GLOBOCAN 2008; NCI Surveillance Epidemiology and End Results (SEER); National Comprehensive Cancer Network (NCCN) Guidelines for Patients; ClinicalTrials.gov; breastcancer.org; CRI grantee progress reports and other CRI grantee documents



[1] Friedman LM et al. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc Natl Acad Sci U S A 2005; 102: 1915-1920. Access PDF

[2] Bargmann CI, Hung MC, Weinberg RA. The neu oncogene encodes an epidermal growth factor receptorrelated protein. Nature 1986. 319:226-30; Schechter AL, Hung MC, Vaidyanathan L, Weinberg RA, Yang-Feng TL, Francke U, Ullrich A, Coussens L. The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science 1985. 229:976–978.

 

 

Breast Cancer News & Stories

  • Meet the YP Fellow: Jing-Ping Hsin, Ph.D.

    Context is everything. That is as true for cells as it is for sentences. CRI’s latest Young Philanthropist (YP) Fellow, Jing-Ping Hsin, Ph.D., will be testing the role of context on gene expression in cancer.

    September 18, 2014

  • Cancer Research Institute to Honor Leaders in Cancer Immunotherapy

    Murdo Gordon of Bristol-Myers Squibb and CRI Trustee Jacques C. Nordeman will receive the Oliver R. Grace Award at Cancer Research Institute’s 28th Annual Awards Dinner.

    September 16, 2014

  • 32 Years and Counting

    CRI trustee Jacques Nordeman has been steering the course against cancer for more than three decades.

    September 16, 2014

Reviewed By:

Leisha Emens is an expert in breast cancer immunotherapy
Leisha A. Emens, M.D., Ph.D.
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD

Support Breast Cancer Research

A donation to the CRI today will help us to fund groundbreaking scientific research aimed at bringing safe and effective immune-based treatments to patients with breast cancer.

Donate Now

Cancer Immunotherapy Clinical Trial Finder

Cancer Immunotherapy Clinical Trial Finder

Are you a patient interested in enrolling in a cancer immunotherapy clinical trial? Visit our Clinical Trial Finder page to learn what trials you may be eligible for.

Learn More

Webinar on BREAST and pancreatic Cancers

Listen in as Dr. Elizabeth Jaffee discusses the latest immunotherapy research for breast and pancreatic cancers in this 45-minute webinar recording.

Watch Now

Stay Informed About Breast Cancer Breakthroughs

Subscribe to our e-updates to receive the latest news about breast cancer immunotherapy.

Sign Up Today

Dr. Haihui Lu Studies How Breast Cancer Cells Hijack the Immune System

Haihui Lu

As a postdoctoral fellow funded by CRI, Dr. Lu is forging new knowledge on how breast cancer tumors "hijack" macrophages to facilitate cancer metastasis and immune evasion.

Read More