A southwest oncology group study on the use of a human tumor cloning assay for predicting response in patients with ovarian cancer

Abstract

A total of 211 patients with epithelial ovarian cancer (168 with tumors refractory to prior chemotherapy and 43 with no prior chemotherapy) from 33 different Southwest Oncology Group institutions had their tumors sampled and specimens shipped to two central laboratories for drug-sensitivity testing in a human tumor cloning assay. The 168 patients with a prior history of chemotherapy failure (median of four prior chemotherapeutic agents) were treated with the most effective agent(s) found in the cloning assay (23 patients), and those patients whose tumors did not form colonies in vitro or did not manifest any sensitivity to agent(s) were treated with a clinician's choice of agent(s) (101 patients). The remaining 44 of the 168 patients were not treated with chemotherapy because of deteriorating performance status or early death. The complete and partial response rate in patients treated according to assay results was 28% versus 11% for the patients treated according to clinician's choice (P = 0.03). There was no statistically significant difference in survival between the two options (6.25 versus 7 months, respectively). The 43 patients with no history of prior chemotherapy were all treated with standard combination chemotherapy, and their clinical response was compared with their in vitro sensitivity to the same agents. Overall there was a 100% true-positive rate and 100% true-negative rate for the seven evaluable patients. From these data the authors conclude that use of the human tumor cloning assay may increase the response rate but not the survival for selected patients with advanced chemotherapy-refractory ovarian cancer. The study is weakened, however, by the many steps of patient selection necessitated by inadequate tumor colony formation in vitro and the inability to treat all patients (because of early death or a rapid decline in performance status). The assay does appear to be worthy of additional study for predicting response to combination chemotherapy in patients without a prior history of chemotherapy. Finally the use of central chemosensitivity testing laboratories is feasible for testing in vitro predictive assays in a cooperative group setting.

Precision medicine for cancer with next-generation functional diagnostics

“…‘First-generation’ versions of these tests, which have been developed and intensively studied over the past 30–40 years, can be divided into a number of categories; a comprehensive review of these older tests is beyond the scope of this article and is well summarized in recent commentaries 18–20 . The earliest of these include the human tumour clonogenic assay (HTCA) 21 , differential staining cytotoxicity (DiSC) assay 22 , extreme drug resistance assay (EDRA) 23 , ChemoFx assay (Helomics, Pittsburgh, Pennsylvania, USA) 24 and subrenal capsule assay (SRCA) 25 . Several of these protocols, such as HTCA and ChemoFx, grow the patient’s tumour cells until homogeneous tumour colonies or lines are generated; the viability of these cells is then tested after exposure to chemotherapeutic agents using assays such as cell counting, metabolic tetrazolium dye (MTT) or whole-cell ATP-content-based readouts of cell numbers.…”

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma

“…The ATP tumor chemosensitivity assay (ATP-TCA) described here is a new generation assay. Previous chemosensitivity assays have been dogged by technical difficulties over the past 25 years [11,12], though several have shown potential in clinical trials [13]. The ATP-TCA compares favourably with all previous methods in terms of standardisation, evaluability, tumor cell number required, reproducibility and accuracy.…”

Prediction of survival in patients with head and neck cancer using the histoculture drug response assay

“…The procedure was envisioned as analogous to determining antibiotic sensitivity in bacterial disease. However, implementation of a cancer drug response assay has proved arduous, and the problems are far more subtle than for assessment of antibiotic sensitivity 3–8. Major problems arose from issues related to tissue culture conditions that are radically different from the normal environment of the tumor cells.…”

“…Major problems arose from issues related to tissue culture conditions that are radically different from the normal environment of the tumor cells. 3–8 The histoculture drug response assay (HDRA) solves many of the previously encountered problems with in vitro testing. Most importantly, it maintains the three‐dimensional tumor‐tissue histology in culture.…”