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DNA Repair to Develop Response Test For Head/Neck Cancer Chemotherapy

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DNA Repair Company is planning to develop a diagnostic test that gauges which head and neck cancer patients will benefit from chemotherapy treatment, based on promising results from an early clinical trial identifying new response biomarkers in this patient population.
 
The Boston-based personalized cancer treatment firm, in collaboration with researchers at the University of Chicago Medical Center, has identified new biomarker combinations that may be predictors of response and overall survival in the treatment of head and neck cancer with induction chemotherapy.
 
The company reported last week that the combination of two DNA repair markers, XPF and pMK2, “significantly correlated with response to therapy and overall survival better than XPF or pMK2 alone.” A preliminary algorithm based on three DNA-repair markers “also produced superior results,” DNA Repair said in a statement.
 
Although further confirmatory studies need to be completed, DNA Repair CEO Daniel Paterson claimed that the biomarkers identified by the company will allow physicians to identify head and neck cancer patients expected to respond to chemotherapy with as much as 90-percent accuracy.
 
Lead investigator Tanguy Seiwert from the University of Chicago Medical Center presented the study data at the American Society of Clinical Oncology’s annual meeting in Chicago earlier this month.
 
DNA Repair “intends to develop and market a diagnostic for this indication,” Paterson told Pharmacogenomics Reporter this week. While the company currently plans to develop the test on its own, it “is constantly assessing potential partners,” Paterson added.
 
The Study
 
According to the study authors, recent analysis of the nucleotide excision repair pathway found that ERCC1 gene expression can predict how an individual with multiple tumors will respond to platinating agents — commonly prescribed chemotherapies, such as carboplatin and taxane, used against various cancerous malignancies. Researchers from the University of Chicago Medical Center and DNA Repair performed a more comprehensive analysis of the six inter-related DNA repair pathways to identify clinically promising DNA repair biomarkers specifically in head and neck cancer.
 

“With these clinical biomarkers, physicians will be able to predict who will respond to treatment with 90 percent accuracy.”

The researchers analyzed 73 FFPE tumor samples from locally advanced head and neck cancer patients treated with carboplatin/taxane induction, followed by FHX-based chemoradiotherapy. Immunohistochemistry staining was performed on eight DNA repair biomarkers, or five of the pathways (ERCC1 (clone 8F1), XPF, pMK2, PARP, PAR1, pH2AX, MLH1, FANCD2), as well as associated markers Ki67, EGFRvIII, and p16. The IHC results were analyzed through automated image processing, and by two blinded pathologists.
 
In the study, nuclear/cytoplasmic intensity/quantity scores were correlated with response/survival and antibody specificity was determined through immunoblot analysis.
 
The researchers found that ERCC1, which has been shown in previous studies as a response predictor for platinating agents in certain tumors, did not in fact predict response and was “marginally related” to overall survival.
 
However, “low levels of XPF were associated with response to induction chemotherapy,” the researchers said in the study abstract. And while pMK2 did not correlate with induction, it was a predictor for overall survival, which suggests that “pMK2 may relate to [FHX-based chemoradiotherapy].”
 
Additionally, “an unsupervised cluster analysis” suggested to researchers that ERCC1 and pMK2 pathways may be related.
 
With this study, the researchers determined XPF to be a novel predictor of response to induction chemotherapy, and a better predictor than ERCC1. Also, the pMK2 marker differentiated a subgroup of patients with improved survival and could be potentially related to FHX-based chemoradiotherapy.
 
“Further study of pMK2 is needed,” the researchers concluded. “Analysis of multiple DNA repair markers holds promise.”
 
Staining of 50 patients undergoing carboplatin/taxane induction therapy followed by FHX-based chemoradiotherapy and of 40 patients on just FHX-based chemoradiotherapy is ongoing.
 
Improving Outcomes
 
DNA Repair believes that its integrated multiple-pathway analysis of DNA repair markers can help physicians choose the optimal treatment for head and neck cancer patients and improve patient outcomes.
 
“DNA repair biomarkers, used in conjunction with one another increased the likelihood of distinguishing responders from non-responders to chemoradiotherapy treatments,” the company said in a statement.
 
The current standard of care is a combination of chemotherapy, radiation therapy, and surgery. The standard chemotherapy for this indication is platinum-based chemotherapy, such as cisplatin, carboplatin, and taxane-based drugs such as Taxol or Taxotere.
 
According to DNA Repair’s Paterson, in the company’s study, without clinical biomarkers approximately 30 percent of patients responded to chemotherapy while 20 percent had no response.
 
“DNAR identified three individual markers, which stratified patients into two groups: those who are likely to respond to therapy and those who will not,” Paterson said. “With these clinical biomarkers, physicians will be able to predict who will respond to treatment with 90 percent accuracy.”
 
DNAR will be conducting several larger studies to confirm the findings from this study, Paterson said. If confirmatory studies are successful, DNA Repair will then move ahead with its diagnostic development plans for the indication.
 
According to the National Cancer Institute, head and neck cancers account for between 3 percent and 5 percent of all malignancies in the US. These cancers, which most commonly manifest in the oral cavity, salivary glands, paranasal sinuses and nasal cavity, pharynx, larynx, and lymph nodes in the upper part of the neck, are more common in men and in people over age 50.
 
The NCI estimated that in 2005, there were approximately 39,000 people in the US with head and neck cancer. Tobacco and alcohol use are the greatest risk factors for this type of cancer. According to the NCI, 85 percent of head and neck cancers are linked to tobacco use.

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