Breast Cancer Treatment in 10 Years: George Sledge, MD, Offers His Predictions
In a keynote lecture during the 2013 Breast Cancer Symposium breast cancer expert and ASCO Past President George Sledge, MD, offered five predictions for the future of the medical management of breast cancer. Dr. Sledge is now Chief of Oncology at Stanford University School of Medicine, Palo Alto, California.
Dr. Sledge first acknowledged the inherent riskiness of making predictions, which in oncology can be blamed on the fact that “one dumb cancer is worth 10 smart oncologists,” according to Dr. Sledge. He also suggested that predictions fail because they are based on “unsubstantiated bias that is mistaken for hypotheses.”
These caveats aside, Dr. Sledge said he sees five emerging trends that may well shape the future of cancer care in 5 to 10 years. These predictions are based on biology, technology, economics, and demography, all of which “intersect in the deep dark woods of the modern health-care system.”
Prediction #1: “The era of HER2 is almost over.” “We will always have patients relapsing with HER2-positive disease, and this will require novel therapies,” Dr. Sledge said. “But from a public health standpoint, I believe HER2 is almost over.”
This prediction is based on the fact that with adjuvant ado-trastuzumab emtansine (Kadcyla) plus pertuzumab (Perjeta), 3-year disease-free survival may exceed 92% (according to the schema for the current trials). Surpassing this 92% disease-free survival benchmark makes HER2-positive breast cancer akin to testicular cancer, no longer thought of as a “public health issue,” he said. With long-term disease-free survival accomplished, the research questions then become about issues such as toxicity and cost-effectiveness of treatment, and phase III trials will be too expensive to explore these remaining “fill-in-the-blanks” questions, Dr. Sledge said.
Prediction #2: “BRCA testing will become ubiquitous.” This will occur as a result of less expensive assays. The Supreme Court’s invalidation of the Myriad patent opened the door to market forces that will reduce the cost of testing to under $100, Dr. Sledge predicted. “When price is no barrier, we will likely see a surge in BRCA testing (possibly in all breast cancer patients), and the downstream effects of this will be more imaging, more prophylactic surgery, and a modest reduction in systemic treatment because of interventions that occur before the medical oncologist is needed,” he noted. “[Genome-wide] testing will be next, and this will affect everyone’s practice.”
Prediction #3: “We will continue to target proliferation and survival pathways.” Recurrences are thought to be the result of proliferating micrometastases (especially in early recurrences) and activation of dormant cells (especially in late recurrences). “We haven’t gotten rid of this problem. It’s safe to say that targeting proliferation will continue to be important,” he said. Novel pathway inhibitors, such as the experimental compound PD0332991 targeting cyclin-dependent kinases, affect cell-cycle progression and hold great promise.
Prediction #4: “Cancer genomics will become ubiquitous, but we won’t like what we find.” The cost of genomic testing will fall enough to make assays readily usable in the clinic, but the implications of this for patient management are concerning. Recent studies in breast cancer samples found driver mutations in at least 40 different cancer genes, with as many as six driver mutations in some tumors. This is daunting for treatment and for drug development. “In the history of cancer, we have never targeted six drivers intentionally,” he noted.
Beyond the “top fliers,” like p53 and PI3 kinase, most are rare mutations. “To think of treating these tumors in a way that has been successful, like targeting kinases, means we will have to be very clever,” he said. Just as discouraging is the prospect of designing trials of relevant treatments for what becomes an orphan disease. In addition, rapid emergence of compensatory mechanisms of resistance to virtually all drugs, along with the expense and toxicity of combining several biologics, will create further hurdles.
Prediction #5: “We will need to do something different.” Relapses that occur beyond 5 years in estrogen receptor–positive patients are likely the result of dormant micrometastases. “This is a challenge for which we do not yet have good solutions,” Dr. Sledge said. The targeting of proliferating cells may not affect dormant cells; as agents are better able to suppress proliferating cells, dormant cells will become the major cause of breast cancer death and the remaining challenge in breast cancer, he predicted.
Dormancy could be addressed by increasing the duration of hormonal therapy, an approach recently validated by large endocrine therapy trials; by improving the detection and prediction of dangerous dormancy (for instance, by advancements in imaging, plasma DNA, and RNA assays); and by developing novel therapies specifically against dormant cells, possibly through immune modulation. “Novel ways of targeting stem cells might not work in the overtly metastatic setting, but could possibly be game-changing in the adjuvant setting,” he suggested.
Dr. Sledge concluded his lecture with a quote from the science fiction writer Arthur C. Clarke: “If an elderly but distinguished scientist says that something is possible, he is almost certainly right; but if he says that it is impossible, he is very probably wrong… You notice I didn’t say that anything here is ‘impossible.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
