Breast cancer, like nearly all cancers, is caused by acquired genetic changes, i.e. mistakes copying DNA. People are often skeptical when I tell them their cancer is caused by a mistake copying DNA. There are about 6 billion nucleotides that make up the DNA in each cell. Whenever a cell divides all 6 billion nucleotides must be copied to make new DNA for the new cell. If you have made a mistake dialing a phone number or spelling a word then you can understand that DNA Polymerase could make a mistake copying 6 billion nucleotides.
Once you accept the idea of cancer as an acquired genetic disease you begin to wonder: In which genes do these mistakes occur and how do these genetic changes cause cancers?
In general the genetic mistakes that cause cancers occur in genes that control cell division, “programmed cell death” or DNA repair. The easiest mistakes for me to understand are those that occur in genes that control cell division leading to uncontrolled cell division and cancer. This concept was understood in the 1980’s at which time a decades-long search for treatments to act on the abnormal genes and their products began.
One of the genes involved with the control of cell division is the mTOR gene. The product of this gene is an enzyme (a serine-threonine kinase) that adds a phosphate group to other proteins when activated. This enzyme catalyzes one of a series of reactions in a pathway that leads to cell division. In many cancers one of these enzymes is defective, leading to uncontrolled cell division. The mTOR gene product is neither the first nor the last step in this pathway, located somewhere in the middle. Upstream molecules include Her-2/neu, EGFR, PI3K, pTEN and AKT.
Everolimus is an oral mTOR inhibitor that blocks the enzyme encoded by the mTOR gene, blocking this pathway. One would predict that cancers caused by activation of the pathway prior to mTOR would stop growing under the influence of everolimus, while cancers caused by activation of the pathway after mTOR would be resistant.
G Hortobagyi et al (JCO Feb 10, 2016 vol 34 No 5 p 419) attempted to correlate responses to everolimus with the genetic makeup of the breast cancer being treated in patients with metastatic breast cancer. They specifically looked for a correlation between activation of molecules upstream from mTOR and response to everolimus. They report very little correlation, meaning we cannot predict which patients with metastatic breast cancer will respond to everolimus.
The inability to predict which patients should try everolimus is disappointing, but not surprising in light of the complexity of the genetic pathway everolimus blocks.
The FDA has approved everolimus for 2nd line treatment of estrogen-receptor-expressing metastatic breast cancers in combination with exemestane. We have seen dramatic responses to this combination, including a patient seen last week. The paper cited above tells us we do not yet know enough about the mTOR pathway to predict which patients will respond based on the genetic profile of their tumor. So this combination may be considered as a second treatment for any patient with metastatic breast cancer expressing the estrogen receptor.
We are also participating in S1207, a trial of adjuvant everolimus with hormonal therapy in women with “high-risk” breast cancer that expresses the estrogen receptor but does not over-express Her-2/neu. These patients may choose to participate in a clinical trial that randomly assigns to receive the hormonal treatment of their choice with or without everolimus. This treatment is administered after a surgeon has removed all visible cancer and following "adjuvant" chemotherapy.