Carsten Kampe, MD, PhD, FACP
Medical Oncologist, Hematologist/Texas Oncology
Twenty years ago when I was a mere MD PhD fellow at UCLA growing cancer cells in Petri dishes, with lofty hopes of making inroads against cancer, I had little idea just how far we would come in the next couple of decades – or that Dr. Slamon, who’s lab was down the hall from mine, would be instrumental in the development of Herceptin, a major breakthrough for a subset of breast cancers. My project involved enhancing immunogenicity in human cancer cells by gene transfer, the Holy Grail, in my mind, of enhancing the body’s own immune system to fight off cancer. Alas, I would go on to leave the laboratory and focus on patient care in Austin, Texas and Dr. Slamon would go on to receive well-deserved acclaim for his remarkable research results. But I would also be on the front lines putting into practice his, and the pioneering work of many other dedicated scientists and researchers, and witnessing some truly spectacular results benefitting our family of patients touched by breast cancer.
Most of us recognize by now that cancer is not a single disease and that it will take many different plans of attack, from many different angles, to impact this dreaded disease. Progress takes time and often comes in baby steps. It is not surprising that there is a collective frustration with what may appear as a lack of advancement in the field. People are more than ready to see real progress, especially when so much money appears to have been spent on research. We’re getting tired of old mantras like those drummed into our consciousness over the last 40 years, for example, that early detection saves lives, when the science behind mammograms has shown, at best, a marginal benefit. The hunger for more substantive progress is almost palpable. We should do better, and we can do better. So, where have we made progress?
How about prevention? Can’t we just keep cancer from ever rearing its ugly head in the first place? Fortunately, with the advent of mapping the human genome this goal is becoming more of a reality. We are learning more about how genes influence breast cancer and can already identify individuals at high risk who can benefit from chemoprevention with drugs like Tamoxifen. Fenretinide, a drug related to vitamin A, is showing similar promise, and is under active study. Other studies, such as the Sister Study and the Two Sister Study, are continuing to find lifestyle factors that may impact risk, including exercise, weight control, and diet.
How about getting away from old school practices of “one size fits all” treatment in breast cancer? Not everyone with breast cancer needs chemotherapy. Scientists have developed genomic profiling techniques that are now used routinely to help determine who will and who will not benefit from chemotherapy. Consequently, many patients have been spared the toxicities of this rather barbaric treatment, whereas those who receive it can be reassured that they are likely receiving benefit.
How about progress in surgery? Not long ago, surgery for breast cancer was often quite disfiguring. Fortunately, newer surgical techniques, including oncoplastic and microvascular surgery, are being used to leave patents with better cosmetic outcomes.
How about radiation therapy? Newer techniques, such as hypofractionated radiation and accelerated partial breast irradiation, are being studied to determine if they work as well as standard whole breast radiation. They have the advantage of reducing time spent by the patient in the radiation suite.
What about chemotherapy drugs? Are we any closer to considering these historical, outdated, treatments? Indeed, the focus is turning away from the development of even more cytotoxic agents to the development of targeted agents that exploit weaknesses in the growth and progression of cancer cells. For example, PARP inhibitors are being studied in the hopes of treating cancers with BRCA mutations and those that do not respond to other drugs.
How about other targeted therapies? Since the development of Herceptin, which targets the erbB2 receptor on Her-2/neu over-expressing breast cancer cells, we have witnessed the arrival of several new and highly effective anti-HER2 therapies, including lapatinib (Tykerb), pertuzumab (Perjeta), and the antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla). The science behind the Trojan horse-like molecule, Kadcyla, is nothing short of phenomenal. Anti-angiogenesis drugs are also being studied with the hopes of starving cancers of a blood supply.
How about hormonal therapies: Is there room for improvement for this older class of drugs? Indeed, there is. One of the major breakthroughs in the recent past was evidence that showed that Everolimus (Afinitor) could effectively reverse the resistance of cancer cells to hormonal therapy. Giving extra mileage to hormonal therapy was a welcomed advance for patients whose cancers respond to this line of attack.
How about our patients with metastatic breast cancer – who are in a league of their own – what progress is being made for them? How about attacking metastases – the process responsible for causing death in patients with breast cancer? Personalized medicine is being applied here, too. Studies are beginning to show that women diagnosed with metastatic breast cancer live longer without the cancer growing when they get treatments based on molecular profiling results. Earlier this month, researchers reported on a gene, called ATF3, that may be a crucial link between stress and cancer, including metastatic spread of cancer. ATF3 promotes the immune cells recruited to the site of cancer to act erratically and give cancer an escape route from a tumor to other areas of the body. This stress gene might one day function as a drug target to combat cancer metastasis. The drug decitabine is also being studies for its ability to turn on a gene coding for protein kinase D1 (PRKD1) that halts the ability of cancer cells to separate from a tumor and spread to distant organs. These are only two examples of extensive research going on in this area.
So, whatever came of gene therapy?
Meanwhile, back at UCLA, the same research using gene therapy that I helped start two decades ago, is still alive and well. In fact, last week UCLA professor Noriyuki Kasahara, MD, PhD, published his results on a new therapy strategy for breast cancer that has spread to the brain. He showed that with gene therapy, genetically modified cancer cells are killed by a drug called 5-FU. To get the gene into the cancer cells, the researchers first inserted it into a virus that can infect tumor cells. After the virus has infected the cells, nontoxic 5-FU is given to the patient. Tumor cells infected by the virus convert the nontoxic drug to a toxic form that kills the cancer cells. If that doesn’t send chills down your spine then, well, I don’t know what to say.
As for me, I see this as yet another of many areas of great hope in our fight against breast cancer and see the future of breast cancer research as bright and hopeful. Our responsibility to make progress against this all too common disease and to favorably impact the lives of women in all stages of the disease is great. While no longer in the laboratory plugging away at breakthroughs, big or small, it is still my honor to be a part of this journey and to celebrate each step – baby step or giant leap – with our breast cancer community. Bless you all!
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