Not Responding to the Standard Cancer Treatment? Maybe You’re an Outlier

In a recent reply to a blog comment, I mentioned the term “outlier” to describe a woman with breast cancer who had an excellent response to bevacizumab-based therapy. This was part of a discussion about the drug and its role in cancer treatment. The term outlier was utilized to describe this woman’s excellent response to a drug combination that has not achieved statistically significant survival advantage in the general population of breast cancer patients.

While outliers may connote strangeness or removal from the norm, in contemporary cancer therapies being removed from the norm can be a very, very good thing. After all, a minority of cancer patients benefit durably from chemotherapy. Those patients fortunate enough to have long-term responses are the happy outliers who populate the scientific community’s grab bag of anecdotes.

However, to the individual patient, a good response is much more than an anecdote, it is a life saving experience, an experience that every cancer patient richly deserves. While clinical trials are designed to identify average improvements for average patients, virtually every trial conducted has patients who live much longer than average. They constitute the tail on the survival curve and almost every trial has several.

Our job should be to identify those true responders and treat them appropriately rather than denying them active treatments based on the failure of the average patient paradigm. In statistics, the term applied for these failures are “beta errors,” meaning that the investigators missed the benefit of a given treatment. By identifying active treatments in small subsets of patients, functional analytic tools (like the Rational Therapeutics EVA-PCD platform) enable us to select those small subsets for treatment regardless of average expectations.

What’s Wrong with Avastin?

Nothing really. It’s a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman, MD, at Harvard University. Dr. Folkman reasoned that:

  1. Cancers require oxygen and nutrients
  2. These would need to be delivered by a blood supply
  3. Tumors would avidly seek their own blood supply via humoral factors.

His groundbreaking work ultimately lead to the discovery of VEGF, as well as the FDA approval of Avastin, the monoclonal antibody that binds and inactivates circulating VEGF in patients. The problem isn’t with Avastin, it’s with the practice of oncology – the clinical trial process and the muddied waters that surround clinical utility of any drug, new or old.

There are no perfect drugs. There are simply drugs that work for certain patients. VEGF down-regulation is an attractive and highly appropriate therapy for a subset of cancer patients with many different diagnoses whose tumors use the VEGF pathway to their advantage. Avastin combined with carboplatin and taxol has improved the survival of lung cancer patients. Avastin plus folfox has improved survival for colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesn’t improve the survival of all breast cancer patients.

When the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change. The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some breast cancer patients are missing out on a treatment that could quite possibly save their lives.

One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another. Our solution to this problem has been to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome. Our results to date in patients with non-small cell lung cancer, colorectal cancer and even rare tumors (like medullary carcinoma of the thyroid) suggest this to be a highly productive direction for future development.