It has long been known that obesity and elevated cholesterol are risk factors for breast cancer and even decrease the efficacy of certain standard therapies. A new finding published last week in the journal Science and summarized by The Washington Post sheds some light on why that might be, and proposes a new use for an old-fashioned drug that could disrupt the oncology market. Believe it or not, your run-of-the-mill statin, like AstraZeneca's (NASDAQ:AZN) Crestor, could find a new home on the shelves of oncology clinics.
Three cancers, three treatments
It's unfortunate that within the realm of breast cancer there are three different etiologies of disease -- and therefore three different courses of treatment.
The most common variant, Estrogen Receptor Positive (ER+), is characterized by a hypersensitivity to the hormone estrogen, which can cause tumors to grow and spread throughout the body. Theoretically, blocking the estrogen response should quell tumor growth in ER+ patients. Tamoxifen, for example, is marketed by AstraZeneca as Nolvadex and blocks estrogen receptors to prevent recurrence. AstraZeneca also markets Arimidex, which blocks estrogen production and brought in $543 million in 2012.
About a quarter of breast cancer patients show extra activity of human epidermal growth factor 2 (HER2+), and don't really respond to drugs used to treat ER+ cancers. HER2+ breast cancer is the target of Roche's (OTC:RHHBY) Herceptin, which has proven a huge source of revenue for the company, garnering $5.9 billion in 2012. To improve the treatment and protect against biosimilars, Roche and Immunogen have collaborated to produce Kadcyla. Kadcyla is one of a new class of drugs that fuse targeted antibodies, like Herceptin's active agent, to tumor killing small molecules. It was approved by the FDA in February, and neither company has provided a clear picture yet on the success of its launch.
A smaller proportion of breast cancer patients are "triple negative" (ER-, HER2-, and progesterone negative), and are much more difficult to treat using targeted therapies. On Monday, Celldex Therapeutics (NASDAQ:CLDX) announced the initiation of a phase 2 program to study CDX-011 in patients with metastatic triple negative breast cancer. Like Kadcyla, CDX-011 is a drug-antibody conjugate, and the prospect of accelerated approval has made it a major draw for investors, helping to send the stock up almost 300% year to date.
The new findings
Researches at Duke discovered that when they transplanted human breast cancer tissue into mice with elevated cholesterol the tumor cells grew more quickly than in normal mice. They also showed that ER-positive tumor cells have higher levels of the enzyme CYP27A1, which converts cholesterol to a molecule called 27HC, and that 27HC actually mimics the effects of estrogen to promote tumor growth.
It stands to reason, then, that blocking CYP27A1 may be useful in treating ER+ breast cancer by blocking faulty estrogen signaling, but without the hormonal side effects of other therapies. That appeared to be the case, as blocking the enzyme in a mouse model of breast cancer slowed disease progression. Granted, the idea of CYP27A1-targeted therapies is in its infancy, but keep an eye out as experimental therapies move through preclinical studies and into early stage trials.
But that's years away. What about now?
One approach that is gaining traction is to reduce 27HC indirectly by reducing total cholesterol, and we already have a slew of drugs that do that. Pfizer's Lipitor, for example, is a statin that was at one time the best-selling drug in the world. Now, AstraZenpca's Crestor takes the cake as the most potent of the branded statins. I wouldn't be surprised to see more early stage trials pop up looking closely at the market opportunity for statins in breast cancer prevention and treatment. In fact, a Phase 2 trial at the National Cancer Institute is currently under way examining biomarkers for disease risk in women treated with Lipitor.
While these scientific advancements have the potential to disrupt the ER+ breast cancer market, they'll do little to help women at risk of HER2+ or triple negative breast cancer. The different molecular make-up of those cancers means that estrogen, and consequently 27HC, are less important in disease progression. Roche should remain at the forefront of HER2+ therapies, and Celldex's platform may emerge as the first viable option in many years for women with tripl- negative breast cancer.