Although many drugs are under study for patients with metastatic breast cancer, there is a pressing need to establish methods of predicting response and improving drug delivery, and researchers are looking toward molecular imaging techniques to help reach those goals.
Pamela Munster, MD
Although many drugs are under study for patients with metastatic breast cancer, there is a pressing need to establish methods of predicting response and improving drug delivery, and researchers are looking toward molecular imaging techniques to help reach those goals, according to Pamela Munster, MD, a specialist in developmental therapeutics.
Munster spoke about these research priorities with a sense of urgency during a recent presentation at the 14th Annual International Congress on the Future of Breast Cancer, which Physicians’ Education Resource hosted on July 16-18 in Huntington Beach, California. Munster, a professor in the Department of Medicine at the University of California, San Francisco (UCSF), leads the Developmental Therapeutics Program at UCSF Helen Diller Family Comprehensive Cancer Center.
Categories of drug development for patients with breast cancer include strategies that target signaling pathways or the cell cycle, immunotherapy, and epigenetics, Munster said. Yet she said that although there are many promising options even for patients who have progressed multiple times, it is difficult to match patients with therapies.
For example, Munster said a typical patient she encounters in her practice is a 64-year-old woman with liver metastases from estrogen receptor (ER)—positive, progesterone receptor–negative, HER2-negative breast cancer who has received adjuvant chemotherapy and metastatic regimens including cytotoxic and targeted treatments.
Taking the next step therapeutically is difficult. “A patient has to make a decision—which drug would she pick?” Munster said. “She may not have the opportunity to pick five different choices. Her time may run out….We have a very intense need for more tailored therapy.”
Novel Imaging Techniques
According to Munster, the need for better drug targeting starts early in the development process. Phase I trials are associated with several challenges, including an inability to predict therapeutic responses and validate the drug target in human patients. Therefore, she stated that target-specific imaging may help validate the treatment target, demonstrate engagement and inhibition of the target, and localize the tumor.
“With more focused imaging, we can get an idea of how the drugs actually get to the tumor,” said Munster.
For instance, Munster noted that data from the BOLERO-2 trial1 showed that the addition of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), to exemestane provided a significant clinical benefit for patients with ER-positive metastatic breast cancer.
However, Munster noted that the ER mutation might not be relevant to this response. Although multiple drugs that inhibit mTOR and other enzymes in the PI3K pathway are currently under study in clinical trials, uncertainty regarding biomarker relevance and the lack of correlation between tumor mutation status and clinical response presents a challenge for introducing these agents into clinical practice, according to Munster.
This question has prompted the development of an early-phase clinical trial using hyperpolarized carbon-13 (13C) in magnetic resonance spectroscopy (MRS) to image liver metastases in patients with hormone receptor—positive breast cancer treated with everolimus. This method investigates the relative MRS signaling intensity of lactate and pyruvate, two products of energy metabolism. Tumor tissue has a higher lactate-to-pyruvate ratio, which is also indicative of increased PI3K activity. According to Munster, a lower ratio of lactate to pyruvate in the tumor tissue following everolimus treatment indicates that the drug is delivered to the tumor and is targeting the intended molecular pathway.
Although a phase I clinical trial has been proposed, this technology has yet to be optimized. Munster noted that the hyperpolarized 13C has a short half-life (about 90 seconds) that has made early experiments challenging. Nevertheless, she indicated that she and her colleagues “are really excited about this technology.”
Munster also described the novel use of Cupper (64Cu) radiolabeled peptides with positron emission tomography (PET) imaging to detect delivery and uptake of MM-302, a HER2-targeted doxorubicin that is delivered specifically to the tumor cell and drastically reduces the cardiotoxicity commonly associated with doxorubicin. According to Munster, administration of 64Cu-labeled MM-302 followed by PET could predict patient response to MM-302, which would help clinicians decide whether to administer the treatment to the patient.
Fluoroglutamine PET has also been introduced as an imaging method for detection of glutamine-dependent tumors that may benefit from CB-839, a glutaminase inhibitor that is currently undergoing investigation in several phase I trials in multiple tumor types including triple-negative breast cancer (TNBC).
Inhibitors of immune system checkpoints such as the programmed cell death-1 (PD-1) and its ligand PD-L1 have shown response rates of 18% to 19% in patients with TNBC in recent investigations, Munster said. However, she said clinical success depends on the expression of PD-L1 on the tumor cells, and that PD-L1 is only expressed in approximately 16% to 25% of breast cancers. CD47 is another immune system checkpoint that has been shown recently to exist in all tumor types. This finding has prompted the initiation of a phase I trial investigating the efficacy of an anti-CD47 antibody in all types of solid tumors, including breast cancer.
However, Munster stated that priming the immune system with epigenetic agents such as histone deacetylase (HDAC) inhibitors prior to immunotherapy might provide an even more effective therapeutic combination. According to Munster, the HDAC inhibitors create a proapoptotic, proinflammatory environment in the tumor, which theoretically activates the immune system to destroy the tumor cells and further increases the efficacy of immunotherapeutic agents. Munster indicated a future trial could investigate the addition of the PD-1 inhibitor pembrolizumab to vorinostat and tamoxifen in patients with ER-positive breast cancer, and another trial could examine the effects of a dual HDAC/PI3K inhibitor in the same patient population.
1. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer [published online December 7, 2011]. N Engl J Med. 2012; 366(6):520-529.