Functional Profiling to Select Chemotherapy in Advanced or Metastatic NSCLC

[gdpawel]

It was suggested in a paper by Dr. Katharina Pachmann that was presented at a recent ASCO trade show, about combining molecular analysis, chemo sensitivity testing in vitro, and therapy monitoring in vivo on disseminated tumor cells (CTC) in breast cancer patients.

Dr. Katharina Pachmann was the investigator who reported at an annual San Antonio Breast Cancer Symposium in 2004, using the CTC technique, German investigators showing that neoadjuvant chemotherapy with paclitaxel (taxol) causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor. The finding helped to explain the fact that complete pathologic responses do not correlate well with improvements in survival (Oncol News Int'l, Vol 14, #5, May '05).

Two years before this, Dr. Christos Kosmas, published a study "Carcinomatous Meningits: Taxane-Induced" which found what is called "dissemination after taxane-based (taxol) chemotherapy. the study concluded that Carcinomatous Meningitis (a CNS metastasis) after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased when compared retrospectivley to non-taxane-treated patients (American Journal Clinical Oncology 2002;63:6-15).

Monitoring CTCs could be utilized for confirmation after the patient is administered assay-directed most beneficial therapeutic agents.

Combining molecular analysis, chemosensitivity testing in vitro, and therapy monitoring in vivo on disseminated tumor cells in breast cancer patients.

Sub-category: Tumor/Cell Biology
Category: Tumor Biology

Meeting: 2010 ASCO Annual Meeting

Session Type and Session Title: This abstract has been published in conjunction with the meeting.

Abstract No: e21116

Citation: J Clin Oncol 28, 2010 (suppl; abstr e21116)

Author(s): K. Pachmann, O. Camara, T. Kroll, S. Carl, N. Rüdiger, C. Rabenstein, A. Plaschke-Schluetter; University of Jena, Jena, Germany; Transfusion Center Bayreuth, Bayreuth, Germany; MMI AG, Zurich, Switzerland

Abstract

Background:

Most breast cancer patients do not die of their primary tumor but from metastases developing sometimes years after the primary tumor has been removed. Cells from the tumor seem to be disseminated continuously during tumor growth and the first spread of tumor cells detectable with conventional methods is in the lymph nodes. Patients with lymph node positive disease have a poorer disease free survival than patients without affected lymph nodes. An increase in circulating epithelial tumor cell (CETC) numbers during adjuvant therapy is correlated with an 11 to 16-fold increase in hazard of relapse indicating increasing resistance to the applied drugs. Therefore, it would be desirable to better characterize these cells, test them for alternate drugs and monitor the actual response to the therapy decided on.

Methods:

For this purpose we have developed a test system comprising isolation of individual CETC from lymph nodes and blood from breast cancer patients for molecular characterization, chemo sensitivity testing of cells from the same sample defining the effectivity of the drugs as percentage of cells killed and measurement of the response of the CETC to the drugs in these patients treated according to guide lines.

Results:

The molecular characteristics and the sensitivity to the applied drugs of the tested cells and the response of the CETC were subsequently compared to clinical outcome.

Conclusions:

The response of CETC to therapy correlated highly with the previously tested chemo sensitivity and the molecular characteristics of these cells. Correlation to relapse or progression free survival is under investigation.

http://abstract.asco.org/AbstView_74_52031.html

[gdpawel]

The November 10, 2012 issue of the Journal of Clinical Oncology published a highly instructive report on the incorporation of Avastin (bevacizumab) and Tarceva (erlotinib) into the treatment of Stage III NSCLC in combination with radiation for the treatment.

The article regarded a pilot study that incorporated an anti-VEGF antibody Avastin (bevacizumab) with EGFR TKI Tarceva (erlotinib) along with chemotherapy and radiation. In this trial the objective response rate of 39 percent, median progression-free survival of 10.2 months and median overall survival of 10.4 months, were not demonstrably superior to contemporary results, yet toxicity was significantly enhanced.

The investigators recommended against further exploration of this combination. Here the aggressive integration of targeted and conventional therapies proved a misadventure.

According to Dr. Robert A. Nagourney of Rational Therapeutics, the trial represented clinicians’ desire to engage in theoretically attractive clinical trials only to find that they reflect ineffective and/or more toxic treatment regimens. This lung cancer experience reflects the failure of the research community to dedicate adequate resources to predictive clinical models.

Combinations of chemotherapy with target therapies have been the subject of investigation at Rational Therapeutics in Long Beach, California for more than a decade. For example, they observed antagonism between platins and the EGFR antagonists Iressa (gefitinib) and Tarceva (erlotinib) two years before publication of the unsuccessful INTACT I and II Trials and three years before the unsuccessful TALENT and TRIBUTE trials.

All four of these trials combined platin based doublets with EGF-TKI’s. More recently Rational Therapeutics successfully identified favorable interactions between Tarceva (erlotinib) and VEGF inhibitors in individual patients that have provided durable responses in their NSCLC patients as first line therapy, now out to four and five years since diagnosis.

These experiences represent opportunities to explore novel therapies and avoid inadvertent antagonisms and misadventures. In the recent JCO, a good treatment was missed while a bad treatment was advanced.

Functional profiling through use of the EVA-PCD assay may represent the critical path from bench to bedside that the deputy director of the Center for Drug Evaluation and Research at the Food and Drug Administration, Janet Woodcock has described as a crying need.

Incorporating Bevacizumab and Erlotinib in the Combined-Modality Treatment of Stage III Non–Small-Cell Lung Cancer: Results of a Phase I/II Trial

http://jco.ascopubs.org/content/30/32/3953.abstract