While the current outlook for most patients with breast cancer (BC) is positive, challenges remain in finding the optimal therapies for the patients diagnosed with metastatic disease, according to Joan S. Brugge, PhD, Harvard Medical School, Boston, Massachusetts, USA, who shared her thoughts on the future treatment of these patients.

Advances in the genetic analysis of tumors have revealed astounding genetic diversity in BC. Multiple alterations are possible, with each patient having individual patterns of alterations. Questions that have emerged include how current therapies are affected by these variable alterations and whether therapies will need to be based on the genetic patterns of each patient. For example, research has shown that human epidermal growth factor receptor 2 (HER2)–targeted therapies are less effective in patients with amplified HER2 and PIK3CA alterations; adding a PIK3CA inhibitor may increase the effectiveness of HER2 therapies in patients with these combined alterations. Dr Brugge said that not all of the alterations influence sensitivity to therapy, and clinicians may be able to stratify patients into a still large but manageable number of subsets, which can be treated with different combinations.

Within each tumor, there may also be significant heterogeneity. Within a tumor, cells that are sensitive to a particular agent will be killed, leaving the surviving resistant cells. This can lead to variable success in the treatment of each tumor within a patient. Recent evidence suggests that a single residual cell can develop into a recurrent tumor. A patient with metastatic BC did not respond to standard chemotherapy and was found to have an activating PIK3CA mutation [Juric D et al. Nature. 2014]. The patient was treated with the PIK3CA-specific inhibitor BYL719 in a clinical trial. After an initial response, the patient developed resistance to the drug and died. Genetic sequencing of metastatic sites showed additional and different PTEN genetic alterations in nonresponding tumors. The fact that these alterations were not present in the primary tumor suggests that a single cell mutated and was able to expand to produce a recurrent tumor in the presence of a drug. Dr Brugge noted the implication that every cell in a tumor must be deleted to prevent regression, which would present a serious treatment challenge.

The most effective tactics of the future will be those that disrupt the tumor ecosystem and block the ability of tumor cells to adapt. This will be a complicated approach requiring multiple agents. One potential strategy is to find the critical nodes of interaction within the tumor ecosystem and target them simultaneously to prevent adaptation. For example, the combination of hormone therapy, a stem cell–targeted inhibitor, a macrophage inhibitor, and a checkpoint inhibitor might prove to be effective. Taking out these nodes would cut off the support system of tumor cells, making them more vulnerable to destruction by the immune system. Another option is to target programs that are “downstream” from oncogenic pathways and pathways activated by microenvironment factors that coalesce to regulate cell survival in the context of cancer therapy, thus preventing “adaptation.”