Novel and Emerging Strategies
Participating in a Clinical Trial
Researchers continually discover and develop promising new ways to fight breast cancer. Once a new treatment is found to be promising from laboratory studies, it is necessary to conduct a series of several types of clinical trials to demonstrate that the treatment is both safe and effective (NCCN 2016). These studies can take years or decades, and until the treatment is approved by the FDA, participating in a clinical trial may be the only way for patients to access these potentially breakthrough therapies.
Participation in a trial can also help each patient ensure that she has access to high-quality clinical care and personalized attention. Patients’ health is carefully monitored throughout the trial. Clinical trials have some risks, too. The new treatment may have side effects or may turn out to be ineffective.
Many women participating in a clinical trial feel very positive about the experience (Wootten 2011). Every patient in every clinical trial advances our understanding of breast cancer and its treatment, and many patients are motivated to participate in hopes that their contribution will help improve future treatment options (Godskesen 2015; Bidad 2016).
Patients should talk with their medical team about ongoing trials that may be appropriate. Women can also consult online resources to learn about ongoing trials:
- National Comprehensive Cancer Network: https://www.nccn.org/patients/resources/clinical_trials/find_trials.aspx
- National Cancer Institute: https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/trial-guide
- American Cancer Society: https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/clinical-trials-matching-service-find-trial.html
Screening, Diagnostic, and Treatment Selection Tests
Three-dimensional (3D) mammography. Three-dimensional (3D) mammography, also called digital breast tomosynthesis, is a newer form of X-ray breast imaging (PDQ Screening Prevention Editorial Board 2017b; Sardanelli 2017). This method uses many images taken from multiple angles to make a 3D-like image (Mall 2017). Initial clinical studies of 3D mammography suggest it may detect more tumors than conventional mammography and reduce the number of women called back for additional testing who turn out not to have cancer (Mall 2017; Rafferty 2013; Ciatto 2013; Giess 2017). The Tomosynthesis Mammographic Imaging Screening Trial began in 2017 and will compare conventional and 3D mammography in about 165,000 women (ECOG ACRIN Cancer Research Group 2017).
Scintimammography. Another emerging imaging technique is called breast-specific gamma imaging or scintimammography (Schillaci 2013; Anonymous 2013). A small amount of a drug that emits radioactivity and accumulates in the breast is injected into the patient (O'Connor 2017). Detection is performed using an instrument called a gamma camera. This test is not being developed for screening the general population, but may be helpful for women whose breasts are not easily assessed by mammogram, such as women with dense breast tissue, implants, or benign conditions (Brem 2016; Yu 2016; Holbrook 2015). Currently, MRI is used along with mammography for these women, but breast-specific gamma imaging may be more effective than MRI. In one recent study, breast-specific gamma imaging was far less likely to suggest a false cancer diagnosis for a patient with only benign lesions (Zhang, Li 2017).
Emerging molecular and genetic tests. New molecular tests may also improve early detection of breast cancer (Tang 2016; Bahrami 2018; Harris 2016). The Videssa Beast proteomics test measures levels of specific proteins in the blood to help doctors interpret the results of imaging tests (Lourenco 2017; Henderson 2016; Reese 2017). This test, when used on women with suspicious mammogram findings, may help determine which women do not have cancer and do not need invasive follow-up procedures (Lourenco 2017). This test may be particularly informative for women with dense breasts that are hard to check with mammograms (Reese 2017).
Numerous multigene molecular tests are also being developed to provide patients and their medical teams with information on prognosis and treatment options (Gyorffy 2015; Duffy 2017; Nicolini 2017). Like the Oncotype DX and MammaPrint tests, these tests analyze tissue collected during the biopsy or surgery. The FDA-approved Prosigna or PAM50 test measures levels of 50 genes to estimate the risk of recurrence for postmenopausal women with estrogen receptor-positive cancer (Gyorffy 2015). The more precise prediction of recurrence risk allows for a better basis for treatment decisions (Ohnstad 2017; Prat 2017). Three additional tests that estimate risk of recurrence—Endopredict, Breast Cancer Index test, and Mammostrat—are commercially available but not yet approved by the FDA (Gyorffy 2015; Mislick 2014).
Circulating tumor cell analyses or “liquid biopsies.” Other new tests, referred to as liquid biopsies, analyze tumor cells or cell-free tumor DNA circulating in the blood. Highly sensitive tests can find this rare material (Wang, Li 2017; Cabel 2017). Liquid biopsies may be helpful for predicting metastasis or determining whether cancer has returned after treatment (Zhou 2017; Cheng 2017).
Liquid biopsies may also be used to find markers of treatment resistance. For example, circulating tumor cells may indicate whether the estrogen receptor has mutated during treatment (Beije 2017). A new mutation may make the tumor cells resistant to endocrine therapy. Similarly, mutations in cell-free tumor DNA may also indicate resistance to a new drug called olaparib (Lynparza) used to treat patients with BRCA2-related breast and prostate cancer (Quigley 2017). Although many patients respond to the drug initially, some become resistant. Researchers have analyzed cell-free tumor DNA from patients who have developed resistance and found new changes in the BRCA2 gene or other DNA repair genes that protect the tumor cells from olaparib (Domchek 2017; Quigley 2017). As these assays advance, researchers are beginning to determine how medical teams can use this type of information to improve treatment selection for patients (Schramm 2016; Khatami 2017). Life Extension Magazine® published an article in 2010 titled “Circulating Tumor Cell Assays: A Major Advance in Cancer Treatment” summarizing the benefits of this revolutionary test.
Cancer cells are prone to DNA mutations. Some of these mutations cause changes that can help cancer cells overcome normal processes that stop cells from growing too fast or dividing when they should not. But too many mutations can be dangerous to cancer cells. Inhibitors of the enzyme poly (adenosine diphosphate-ribose) polymerase (PARP) prevent cancer cells from repairing their DNA when they need to (Nickoloff 2017). Tumors from patients with mutations in the DNA repair genes BRCA1 or BRCA2 often rely on PARP to keep their DNA intact. These patients may be great candidates for PARP inhibitors (Nickoloff 2017; Geenen 2017). The PARP inhibitor olaparib is FDA-approved for treating ovarian cancer (Ohmoto 2017; Kim 2015). In a 2017 phase III clinical trial, patients with a BRCA mutation and metastatic breast cancer treated with olaparib lived an average of seven months without disease progression while patients on standard chemotherapy alone lived only 4.2 months without progression (Robson 2017).
Advances in immunotherapy have already dramatically improved treatment options for diseases such as melanoma (Amaral 2017). Similar therapies are being developed and tested for the treatment of breast cancer (Yu 2017; Mansour 2017; Gentzler 2016). Some key immunotherapy advances in breast cancer are summarized here, and more general information is available in the Cancer Immunotherapy protocol.
Cancer vaccines are one type of immunotherapy that uses material from tumor cells to encourage the immune system to mount a new attack against the tumor (Benedetti 2017). Some vaccines have been tested that direct the immune cells to attack cells expressing HER2 (Yu 2017; Clifton 2016; Mittendorf 2016). One example, called NeuVax, significantly improved 5-year disease-free survival and is being evaluated in a phase III trial (Clifton 2016). Other vaccines in clinical trials target a different protein on cancer cells called mucin 1 or MUC1 (Yu 2017; Antonilli 2016).
Checkpoint proteins are used by healthy cells to control immune response (Solinas 2017). Cancer cells take advantage of these proteins to prevent the immune system from recognizing them as diseased (Yu 2017). Checkpoint inhibitors are drugs that bind to checkpoint proteins, making the target cell visible to the immune system once again. Clinical trials are evaluating several checkpoint inhibitors in breast cancer patients (Mansour 2017; Yu 2017; Vanpouille-Box 2017). Immune checkpoint inhibitors such as pembrolizumab (Keytruda) were found to be safe in phase I trials, with encouraging early responses (Weiss 2017; Brahmer 2012; Nanda 2016).
Bispecific antibodies act as a link between two cell types. One end of the antibody binds to a protein on a cancer cell, and the other end binds to an immune cell (Yu 2017). The immune cell then recognizes the diseased cancer cell and destroys it. One bispecific antibody called armed activated T cells (aATC), which directs T cells to HER2-positive cancer cells, was found to be safe in a phase I trial (Lum 2015). A phase II study in patients with low levels of HER2 is ongoing as of early 2018 (Jagtap 2014).
Photodynamic therapy uses a drug called a photosensitizer that is retained by cancer cells (Banerjee 2017; Lamberti 2014; NCI 2011). The area of the tumor is then exposed to light. The photosensitizer absorbs the energy of the light and produces oxidizing agents that kill the cancer cells. The damage caused by photodynamic therapy also activates the immune system (Maeding 2016). One study used photodynamic therapy to treat women with breast cancer recurrences in the chest wall after mastectomy. Six of the nine treated patients responded well (Morrison 2014). The technique has been tested in mice as a non-invasive way to treat sentinel-node metastases (Shimada 2017). Life Extension Magazine® published an article in 2015 titled “An Alternative to Conventional Breast Cancer Treatment” that further discusses the benefits of photodynamic therapy.
Trastuzumab emtansine, described in the Conventional Treatments section, was the first antibody-drug conjugate (ADC) approved by the FDA for treatment of HER2-positive breast cancer. These drugs use the specificity of the antibody to carefully target chemotherapy to the cancer cells (Deng, Lin 2017; Trail 2017). The ADC sacituzumab govitecan targets a protein called Trop-2, which is an attractive drug target for triple-negative breast cancer cells (Ocean 2017; Sahota 2017; Wu 2011). In a clinical trial of 69 patients who previously tried many different treatments, 30% of participants responded to sacituzumab govitecan. The FDA has granted this drug breakthrough therapy and fast track designations (Bardia 2017; Saha 2016). Another ADC called DS-8201 or trastuzumab deruxtecan targets HER2-expressing cells with a different antibody and chemotherapy than trastuzumab emtansine. In a phase I clinical trial, 43% of participants responded to this drug. Interestingly, even some tumors with only low levels of HER2 responded (Doi 2017). This drug is being tested in additional patients, and the FDA granted it breakthrough status in 2017 (Post 2017).
Researchers are improving current endocrine therapies (described in the Conventional Treatment section) in several ways. For example, studies are evaluating the optimal length of treatment (Blok 2018) and the best patient groups for each drug (Grossman 2018; Heindl 2018). Other studies are examining mechanisms of resistance to endocrine therapies (Castrellon 2017).
Z-endoxifen is an endocrine therapy in development that is similar to tamoxifen (Goetz 2017). Tamoxifen is converted to endoxifen by the liver, but this conversion is inefficient in some patients, and this is one of the factors that explains the reduced benefit of tamoxifen in certain people (Briest 2009; Baatjes 2017). In a phase I study, 26.3% of participants benefited from Z-endoxifen, including three that previously progressed on tamoxifen (Goetz 2017).
Many breast cancers express the androgen receptor, and this includes some breast cancers that do not have estrogen or progesterone receptors (Mina 2017; Rampurwala 2016; Kono 2017; Doane 2006). For women with these tumors, treatment with drugs targeting the androgen receptor may be helpful. Bicalutamide (Casodex) and enzalutamide (Xtandi) are two examples of such drugs, and enzalutamide is being tested in a phase II trial on women with metastatic breast cancer. These drugs are currently approved for treatment of prostate cancer but not breast cancer (Gucalp 2013; Schwartzberg 2017).
Repurposing Existing Drugs
Statins, typically used to reduce cholesterol levels, may improve outcomes in some cancer patients (Haukka 2017; Shaitelman 2017; Manthravadi 2016; Mei 2017). In laboratory studies, statins can inhibit signaling in breast cancer cells and cause cell death (Chan 2003; Lin 2017). A recent meta-analysis of seven studies and almost 200,000 women indicated that statins can decrease all-cause mortality and cancer-specific mortality in women with breast cancer. The authors also noted that primarily a type of statins categorized as lipophilic have this effect. Lipophilic statins include atorvastatin (Lipitor), lovastatin (Mevacor), and simvastatin (Zocor) (Liu 2017).
Metformin is used to treat diabetes, but emerging research suggests it may also mitigate cancer risk and improve outcomes (Sonnenblick 2017; Calip 2015). And metformin has been shown to prevent and reverse drug resistance in breast cancer cells in cell culture and animal models (Davies 2017). One study found that diabetic women taking metformin were less likely to develop breast cancer metastases (Jacob 2016). Another study found that diabetic women with breast cancer who were treated with a diabetes drug other than metformin had worse survival outcomes than those treated with metformin (Sonnenblick 2017). Potential anti-cancer benefits of metformin may not be limited to diabetics (Ko 2015; Pizzuti 2015). In one study, 200 nondiabetic women awaiting breast cancer surgery took either 1,700 mg of metformin or a placebo daily for four weeks. Metformin treatment significantly reduced markers of cellular proliferation in HER-2-positive DCIS in these women (DeCensi 2015). Another study found that cancer cells from non-diabetic breast cancer patients who took metformin before surgery were less active than those from non-treated women (Hadad 2015).