Heterogeneity Complicates Treatment Decisions in Breast Cancer

George W. Sledge Jr, MD

Heterogeneity, which can result in treatment resistance, is commonly underestimated and misunderstood, representing an important area of future research, according to a presentation by George W. Sledge Jr, MD, at the Miami Breast Cancer Conference.

The ubiquitous nature of heterogeneity calls for a number of actions, Sledge explained during his talk. There is a need for better retesting of treatment-relevant biomarkers, a definition for clinically relevant heterogeneity, and improved methods for targeting these alterations. However, the imposing number of molecular alterations seen in cancer represents a significant hurdle.

“There’s a three order of magnitude difference between the least mutated and most mutated cancers. This is true across cancers, but its also true within cancers, to a significant degree,” said Sledge, from Stanford University School of Medicine. “One can only imagine the thousand-fold difference in terms of the number of mutations a cancer carries and those with real clinical significance."

Within breast cancer specifically, mutational burden varies by phenotype. ER-positive tumors generally carry half the mutation burden that is seen in triple-negative breast cancer. Significant differences can even be seen within each subtype, even when exploring just the driver mutations.

In an analysis of 100 breast cancer genomes published in Nature, driver mutations were found in 40 different cancer genes in 73 different combinations. Overall, 28% of these tumors had a single-driver mutation, while the rest had multiple alterations.

“While a little over a quarter had a single driver mutation some had as many as six driver mutations,” Sledge said. “We’ve never intentionally targeted six drivers at one time. This heterogeneity seems to be exceptionally important in how we think about these cancers and how we treat these cancers.”

A number of the testing guidelines have attempted to address heterogeneity, to some degree. The 2013 ASCO/CAP guideline for breast cancer indicates that a tumor is HER2-positive if more than 10% of cells overexpress HER2. Additionally, the guideline states that heterogeneity should be reported, Sledge notes.

“One can see when looking under a microscope a variety of different patterns, it’s not just all negative or all positive,” Sledge notes. “While not as well studied as we would like, it appears to be important.”

The level of heterogeneity at a single-patient level was further illuminated by a study published in Nature that conducted single nucleus genome sequencing on 50 individual cancer cells. The study revealed three different cancers within a single triple-negative breast cancer sample, Sledge noted.

Within the triple-negative breast cancer sample, deep sequencing uncovered 374 clonal mutations, 154 subclonal mutations, and three subpopulations. Approximately a quarter of these mutations (23.44%) damaged protein function.

“This intrapatient heterogeneity appears to be profound,” Sledge said. “Perhaps the most frightening conclusion of this paper was that no two cancer cells within the same cancer have the same genome.”

Adding to the difficulty associated with heterogeneity, discordance exists at every level, including within the primary tumor, between the primary and the metastatic lesion, and even between each metastasis. The sheer number of somatic mutations within a specific tumor defines part of this heterogeneity.

“No matter where you look, whether its estrogen receptor, progesterone receptor, or HER2, there’s discordance seen between primary tumors and metastasis,” Sledge said. “When one is looking at a patient with newly diagnosed metastatic disease, that disease might be functionally and biologically different than the primary tumor.”

Some of the differences seen between the primary tumor and the metastatic lesion are caused by treatment, Sledge explained. In patients with ER-positive disease who receive adjuvant endocrine therapy, mutations in the estrogen receptor that render hormonal therapy ineffective are commonly seen in the metastatic lesion.

“This occurs across a number of studies, approximately 10% to 20% of the time,” Sledge said. “These estrogen receptor mutations are very, very rare in the primary tumor but are reasonably common in the metastasis.”

While a biopsy of multiple metastatic sites is generally hard to obtain in clinical practice, rapid autopsy studies have successfully examined each metastatic lesion within a single patient. Overall, findings showed discordance from one metastatic site to the next. In some situations, one lesion could be deemed HER2-positive while the next was negative.

“What we know, as a result of studies like this, is that there is real heterogeneity here, and we are making treatment decisions based upon inadequate information because of tumor heterogeneity,” Sledge said.

New approaches for detecting and treating molecular alterations are desperately needed to address heterogeneity. A number of potential approaches are currently in clinical trials, Sledge suggested.

“Molecular imaging, which in theory looks at the entire body, might allow us to take a fresh approach to this,” Sledge said. “We need to develop treatments that side-step the genomic instability that troubles us so much.”

Immunotherapy represents a potential approach for overcoming tumor heterogeneity. A number of immune-based approaches are currently under exploration in clinical trials, including checkpoint inhibitors.

A phase I study presented at SABCS looked at treatment with the PD-1 inhibitor pembrolizumab (Keytruda) in 32 patients with metastatic triple-negative breast cancer. In this study, 18.5% of patients experienced a response, with one complete response. At the analysis, the stable disease rate was 25.9%.

“We’re seeing for the very first time immunotherapy approaches for the treatment of breast cancer,” Sledge said, expressing optimism over the SABCS study.

A number of studies continue to explore immune checkpoint inhibition in breast cancer, both in combination with other monoclonal antibodies and following progression on standard targeted therapies. Additionally, studies are exploring PD-1 inhibition in combination with chemotherapy for patients with recurrent metastatic disease.

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