Marker of DNA Damage Could Predict Response to Platinum Chemotherapy

Marker of DNA Damage Could Predict Response to Platinum Chemotherapy:

• Assay could direct treatment options for triple-negative breast cancer.
• Accumulations of telomere AI predicted sensitivity to therapy.

PHILADELPHIA — Scientists have uncovered a marker of DNA damage that could predict who will respond to platinum-based chemotherapy drugs like cisplatin or carboplatin.
These drugs are widely used for ovarian cancer, but as with most cancer drugs, it can be difficult to predict who will respond to therapy.
A team of researchers from the Dana-Farber Cancer Institute found that this marker, telomeric allelic imbalance or tAI, could predict sensitivity to therapy in patients with triple-negative breast cancer.
The results are published in Cancer Discovery, a journal of the American Association for Cancer Research.
“We currently do not have any targeted therapies for patients with triple-negative breast cancer, so if these laboratory findings are confirmed and an assay is created to predict sensitivity to drugs that target defective DNA repair, it would be a major step forward,” said lead pathologist Andrea Richardson, M.D., Ph.D., assistant professor of medicine at Dana-Farber Cancer Institute.
Scientists have long known that DNA repair status is a predictor of sensitivity to therapy and thus prognosis. However, measurements of DNA repair status have been slow to arrive.
Richardson and colleagues looked for genomic signatures in cell lines and tumors and correlated them to platinum sensitivity.
In patients with triple-negative breast cancer, they found that a high level of subchromosomal regions with allelic imbalance extended to the telomere predicted response to cisplatin treatment. The same was true for serous ovarian cancer.
Importantly for patients with triple-negative breast cancer, researchers found an inverse relationship between the level of tAI and BRCA1 expression.

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA 1 by Structural and Functional Assays

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional Assays.

Lee MS, Green R, Marsillac SM, Coquelle N, Williams RS, Yeung T, Foo D, Hau DD, Hui B, Monteiro AN, Glover JN.

Authors' Affiliations: Department of Biochemistry, School of Systems Molecular Medicine, University of Alberta, Edmonton, Alberta, Canada; National Institute of Environmental Health Sciences, Durham, North Carolina; Risk Assessment, Detection, and Intervention Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; and Molecular Biology Program, Institute of Biophysics Carlos Chagas Fo., Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Abstract

Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer....... Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk.

DiaTech Oncology MiCK Chemotherapy Induced Apoptosis Assay Shows Increased Response and Survival in... -- NASHVILLE, Tenn., May 26 /PRNewswire/ --

Findings Published at the ASCO Conference Provide a New Treatment Strategy for Patients and Support Favorable Reimbursement Coverage Policies

NASHVILLE, Tenn., May 26 /PRNewswire/ -- DiaTech Oncology announced today that the American Society of Cancer Oncology (ASCO) has published the results of a comprehensive study to determine the effectiveness of the Microculture Kinetic (MiCK) assay for apoptosis in predicting increased response and survival rates for ovarian cancer patients. In the MiCK assay, the tumor cells of an individual patient are exposed to multiple doses of several chemotherapeutic drugs either as single drugs or in combinations. A sophisticated algorithm is used to monitor and compute the amounts of apoptosis caused by each of the drugs to establish a drug sensitivity profile of the patient's tumor cells. Knowledge of a patient's drug sensitivity profile allows the treating oncologists to prescribe chemotherapy that would be the most effective against the tumor cells of that patient.

The results showed overall survival significantly better in 92% of patients who received the best chemotherapy as predicted by the MiCK assay compared to only 76% of patients who received treatment not recommended by the assay. There was also a significantly higher overall response rate (82% vs. 54%) for patients who received a treatment the assay showed would be preferred. Ovarian cancer patients in stage 3 or 4 and treated with a highly active assay score had significantly increased survival rates (94% vs. 77% alive at 24 months). The clinical benefit rate was 85% for patients with chemotherapy that was highly active in the assay, compared to only 57% for those patients receiving less active chemotherapy.....

Chemoresponse Assay Could Lower Treatment Costs in Ovarian Cancer - ChemoFx

 "...In the study, the authors assumed, for the sake of analysis, that the "outcomes are likely no worse when chemoresponse testing is performed than when an empiric choice of regimen is made."
However, if, in currently ongoing studies, the assay helps clinicians choose more effective therapies and thus improve survival, it would be "very attractive from a health economics perspective," say the authors, because the current study has already shown it to be cost effective."
 
The study was funded by Precision Therapeutics.

Comparison of a novel multiple marker assay vs the Risk of Malignancy Index for the prediction of epithelial ovarian cancer in patients with a pelvic

"CONCLUSION: The dual marker algorithm utilizing HE4 and CA125 to calculate a ROMA value achieves a significantly higher sensitivity for identifying women with EOC than does RMI."

Editorial: A Step Forward for Two-Step Screening for Ovarian Cancer - Journal of Clinical Oncology

A Step Forward for Two-Step Screening for Ovarian Cancer
  Martee L. Hensley, Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY

See accompanying article doi: 10.1200/JCO.19.2484

Chemotherapy time interval and development of platinum and taxane resistance in ovarian, fallopian, and peritoneal carcinomas

OBJECTIVE: To evaluate drug resistance after exposure to neoadjuvant chemotherapy and to postoperative chemotherapy in epithelial ovarian, fallopian, and primary peritoneal carcinomas.

full free access: Clinical relevance of extent of extreme drug resistance in epithelial ovarian carcinoma (repost from Jan 2010)

Note: also note reference materials included in this paper