Cancer Patients Who Get Better, Get Better

JCO coverA study published in the October 20 Journal of Clinical Oncology (Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with Cetuximab, Piessevaux H. et al, 31:3764-3775,2013) described “early tumor shrinkage” as a predictor of long-term survival in patients with metastatic colorectal cancer. These Belgian and German investigators re-analyzed two large clinical trials in colon cancer, CRYSTAL and OPUS, to evaluate the impact of early tumor shrinkage at eight weeks of therapy. Both studies were in patients with wild type (non-mutated) KRAS colon cancer who received chemotherapy with or without the monoclonal antibody Cetuximab.

They used a cutoff of 20 percent tumor shrinkage at eight weeks to separate “early responders” from “non-responders.” Early responders were found to have a significantly better survival. The accompanying editorial by Jeffrey Oxnard and Lawrence Schwartz (Response phenotype as a predictive biomarker to guide treatment with targeted therapies, J Clin Oncol 31:3739-3741, 2013) examined the implications of this study.

The measurement of tumor response has been a lynchpin of cancer therapeutics for decades. This was later refined under what is known as RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Despite this, there remained controversy regarding the impact of early response on long term survival. The current Piessevaux trial however, is only the most recent addition to a long history of studies that established the correlation between tumor shrinkage and survival. Earlier studies in colorectal, kidney, esophagus and lung cancers have all shown that early response correlates with superior outcomes.

What is gratifying in the accompanying editorial is the discussion of the “response phenotype” as a predictor of survival. Phenotype, defined as “the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment” reflects the totality of human biology not just its informatics (genotype). This renewed appreciation of tumor phenotype in oncology is important for it re-focuses on tumor biology over tumor genetics.

The  ex-vivo analysis of programmed cell death (EVA-PCD) that we utilize, is itself a phenotypic platform that measures actual cellular behavior, not gene profiles, to gauge drug sensitivity. We have previously shown that the measurement of chemotherapy effect on human tumor tissue predicts response, time to progression and survival. The current study used clinical response (early tumor shrinkage) to successfully measure the same.

This analysis of early response by Piessevaux is bringing our most sophisticated investigators back to what they should have known all along.
1. Responding patients do better than non-responding patients.
2. Early measurement of response is predictive of long term outcome.
3. These measurements can and should be done in the laboratory.

Taken together, the current study supports early tumor shrinkage and by inference, ex vivo analyses, as important predictors of patient response and survival.

Systems Biology Comes of Age: Metastatic Lung Cancer in the Crosshairs

Cancer therapists have long sought mechanisms to match patients to available therapies. Current fashion revolves around DNA mutations, gene copy and rearrangements to select drugs. While every cancer patient may be as unique as their fingerprints, all of the fingerprints on file with the federal AFIS (automated fingerprint identification system) database don’t add up to a hill of genes (pun intended), if you can’t connect them to the criminal.

To continue the analogy, it doesn’t matter why the individual chose a life of crime, his upbringing, childhood traumas or personal tragedies. What matters is that you capture him in the flesh and incarcerate him (or her, to be politically correct).

The term we apply to the study of cancer, as a biological phenomenon is “systems biology.” This discipline strikes fear into the heart of molecular biologists, for it complicates their tidy algorithms and undermines the artificial linearity of their cancer pathways. We frequently allude to the catchphrase, genotype ≠ phenotype, yet it is the cancer phenotype that we must confront if we are to cure this disease.

Using a systems biology approach, we applied the ex-vivo analysis of programmed cell death (EVA-PCD®) to the study of previously untreated patients with non-small cell lung cancer. Tissue aggregates isolated from their surgical specimens were studied in their native state against drugs and signal transduction inhibitors. This methodology captures all of the interacting “systems,” as they respond to cytotoxic agents and growth factor withdrawal. The trial was powered to achieve a two-fold improvement in response.

At interim analysis, we had more than accomplished our goal. The results speak for themselves.

First: a two-fold improvement in clinical response – from the national average of 30 percent we achieved 64.5 percent (p – 0.00015).

Second: The median time to progression was improved from 6.4 to 8.5 months.

Third: And most importantly the median overall survival was improved from an average of 10 – 12 months to 21.3 months, a near doubling.

These results, from a prospective clinical trial in which previously untreated lung cancer patients were provided assay directed therapy, reflects the first real time application of systems biology to chemotherapeutics. The closest comparison for improved clinical outcome with chemotherapeutic drugs chosen from among all active agents by a molecular platform in a prospective clinical trial is . . .

Oh, that’s right there isn’t any.