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###### Department of Health and Human Services

###### National Institutes of Health 

# AGENCY:

National Institutes of Health, Public Health Service, HHS. 

# ACTION:

Notice.

## Technology Summary 

                    The technology is an exciting discovery in the field of prostate, breast and lung cancer genetic markers having profound clinical applications in defining the optimal chemotherapeutic                           ( print page 24323)                        treatment schedule for each individual patient. This genetic marker (CYP1B1*3) can be potentially used as a prognostic tool to predict survival rate in patients prior to treatment, and to asses their propensity to respond to docetaxel treatment when being treated not only for androgen-independent prostate cancer (AIPC) but also for breast cancer, lung cancer, stomach cancer, head and neck cancer.                 

## Description of Technology or Products 

Prostate cancer develops most frequently in men over fifty. Prostate cancer is the most common type of cancer in the United States, and it is responsible for more male deaths than any other cancer, except lung cancer. The cancerous cells may spread (metastasize) from the prostate to other parts of the body, especially the bones and lymph nodes. 

Prostate cancer is most often discovered by physical examination like digital rectal examination or by screening PSA level in blood. There is some current concern about the accuracy of the PSA test and its usefulness. PSA levels can change due to factors other than cancer. Two common causes of high PSA levels are enlargement of the prostate (benign prostatic hyperplasia or BPH) and infection in the prostate (prostatitis). Screening for prostate cancer using PSA is controversial because it is not clear if the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments. However, prostate cancer is typically confirmed by biopsy. Further tests, such as X-rays and bone scans, may be performed to determine whether the cancer has spread. 

Lung cancer is the most lethal of all cancers worldwide, responsible for 1.2 million deaths annually. Non-small-cell lung cancer (NSCLC) is the most common lung cancer, accounting for about 80% of all lung cancers. Treatment for lung cancer involves surgical removal of tumor, chemotherapy, or radiation therapy, combinations of these methods. The treatment course depends on the localization and the tumor metastasis as well as the overall health status of the patient. Docetaxel was the first drug specifically approved by the FDA for the second-line treatment of NSCLS. 

Breast cancer is the second most fatal form of cancer in females, affecting approximately one out of thirty-nine in the Western world after lung cancer. The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy, chemotherapy, and/or radiotherapy. Docetaxel is most commonly recommended for adjuvant treatment (given with doxorubicin and cyclophosphamide) as it has been shown to be more successful in advanced breast cancer patients than paclitaxel, another drug approved by FDA to treat advanced breast cancer. 

Prostate cancer can be treated by suppressing or blocking androgens with surgery, radiation therapy, hormone therapy, occasionally chemotherapy, high intensity focused ultrasound (HIFU), cryosurgery, or a combination of these approaches. When prostate cells, both healthy and cancerous, are deprived of androgens, they no longer proliferate and eventually die. Surgical removal of the prostate, or prostatectomy, is a common treatment either for early stage prostate cancer or for cancer which has failed to respond to radiation therapy. Unfortunately, prostate cancer usually returns within about 18 months after anti-androgen treatments. In such cases, the condition is referred to as androgen-independent (advanced and metastasized cancer) prostate cancer (AIPC), and the tumors are not responsive to anti-androgen therapy. Currently, physicians recommend chemotherapy for advanced metastatic prostate cancers that have failed to respond to other treatments. However, treatment for AIPC is rapidly evolving. 

Chemotherapy with mitoxantrone and prednisone offers a palliative benefit but no survival advantage. Long-term therapy with this regimen is not feasible due to cumulative dose-related cardiotoxicity. Single-agent docetaxel treatment has shown to be very effective in palliating metastatic prostate cancer and is not associated with cumulative dose-related toxicities. Currently, Docetaxel is one of the most frequently prescribed anti-cancer agents for the treatment of certain forms of breast cancer, lung cancer, stomach cancer, head and neck cancer including AIPC. Despite the relative success of docetaxel in treating AIPC, high variability in clinical response has been observed. Due to variety of available treatment options, choosing the most appropriate treatment can be daunting. Since prostate cancer is a disease of older men who may be frail due to other health issues, many patients die of other causes before the prostate cancer can spread or cause symptoms. Whether or not to treat metastasized prostate cancer with curative intent is a patient's trade off between the expected beneficial and harmful effects in terms of survival time and quality of life. A number of important variables in each patient's history and previous pattern of response must be addressed before choosing effective chemotherapy. Predicting survival rate in patients prior to treatment to asses their propensity to response to docetaxel treatment is one of the most important variables. 

Cytochrome P450 (CYP1B1), up-regulated in tumor cells, is involved in the metabolism of steroid hormones, metabolizing a variety of drugs, and potentially important in prostate tumor development and progression. Several studies have evaluated the relationship between CYP1B1 polymorphisms and risk of various cancers including two common single nucleotide polymorphisms (SNP). These include colorectal, lung, breast, ovarian, and prostate cancers. The difference between wild type and variant type CYP1B1*3 is a single amino acid change at position 432 of the expressed protein caused by a single nucleotide change. Recent studies have shown that this polymorphism is associated with increased risk of advanced prostate cancer and altered drug metabolism. It is known that docetaxel competitively inhibits CYP1B1 mediated processes. The responsiveness and overall survival of patients with AIPC that are treated with docetaxel, can be determined by CYP1B1*3 genotype. In a study of 25 patients after docetaxel treatment, those with AIPC that are homozygous or heterozygous for the wild type CYP1B1*3 exhibited increased (2x) mean survival time compared to homozygous variant. Additionally, there was a similar difference in overall survival observed in 20 men treated with combination estramustine, thalidomide, and docetaxel. Others have found that the CYP1B1*3 allele was the only SNP out of 8 studied variants within 6 genes of known importance in paclitaxel disposition to be associated with lower progression free survival following paclitaxel therapy in 93 patients with breast cancer. Knowledge of an individual's (multiple) phenotypic profile will allow physicians to choose the safest and most effective therapeutic agent. 

This technology has potential utility as a prognostic tool to identify individuals who may benefit from therapy with docetaxel (i.e.  patients that are homozygous for the wild type CYP1B1*3 or heterozygous). 

## Potential Market Size 

                    Prostate cancer is the most common cancer in America, affecting 1 in 6 men. In 2007, more than 218,000 men will be diagnosed with prostate cancer, and more than 27,000 men will die from the disease. In addition to the U.S., approximately 200,000 men in the EU and 32,000 men in UK are diagnosed                           ( print page 24324)                        with prostate cancer each year and the disease accounts for nearly one quarter of all new cancer diagnoses of all new male cancer diagnoses. Worldwide, about 395,000 men are diagnosed with prostate cancer each year and the incidence is on the increase. The total direct medical cost of prostate cancer in the U.S. is $ 5 billion per year. It is estimated that prostate cancer therapeutics in the U.S., Europe and Japan will cost $ 7.3 billion in 2011.                 

The global annual cancer market is estimated at $35 billion with breast, lung and prostate cancers being the most significant contributors. Incidences of lung, breast and stomach cancers were found to be 351,344, 220,000, and 25,000 respectively in the U.S. The current market size of drugs used for the treatment of lung cancer is $ 25 billion, while that of breast cancer is $3.3 billion. 

## Current Competitive Product(s) 

Currently there are no genetic markers available to assess the responsiveness of an AIPC-patient to therapy before starting the treatment. Knowing CYP1B1*3 genetic status saves time and money of patients and prevents ineffective treatments. 

## Value Proposition 

                    The FDA approved dose and schedule for docetaxel in combination with prednisone in the treatment of androgen-independent (hormone-refractory) metastatic prostate cancer is 75 mg/m2                     IV infusion for 1 hour every 3 weeks with 5 mg prednisone continuously and average cost per cycle of therapy is $ 4,298. The use of docetaxel has been recently shown to prolong survival and improve rates of response and quality of life, but it is unclear which patient would benefit from treatment with this drug given that high variability in clinical response has been observed. A consequence of such variability is that a docetaxal treatment may be effective in one subject and ineffective or poorly tolerated in another subject. Thus, administration of such a drug to a subject in whom the drug would be ineffective would result in wasted cost and time during which the patient's condition may significantly worsen. Also, administration of a drug to subject in whom the drug would not be tolerated could result in a direct worsening of the patient's condition and could even result in death. This technology identifies the polymorphism of CYP1B1*3 gene which modulates the therapeutic response to docetaxel treatment. This genetic marker can be measured in DNA obtained from a blood sample to predict overall survival in patients with prostate cancer prior to treatment with docetaxel. Genetic markers with predictive power to assess inter-subject differences resulting in clinical outcome prior to docetaxel administration have profound clinical importance.                 

## Intellectual Property Status 

A PCT patent application was filed 09 September 2006. 

## Partnering Opportunity 

Licensing opportunities are available. In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors. 

*Licensing Contact:*                     Mojdeh Bahar; (301) 435-2950;                     *baharm@mail.nih.gov.*

*Collaborative Contact:*                     John D. Hewes, Ph.D.; (301) 435-3121;                     *hewesj@mail.nih.gov.*

## Next Step: Teleconference 

                    There will be a teleconference where the principal investigator will explain this technology. Licensing and collaborative research opportunities will also be discussed. If you are interested in participating in this teleconference please call or email Mojdeh Bahar; (301) 435-2950;                     *baharm@mail.nih.gov.*                     OTT will then email you the date, time and number for the teleconference.                 

Dated: April 25, 2007. 

Steven M. Ferguson, 

Director,  Division of Technology Development and Transfer, Office of Technology Transfer,  National Institutes of Health.

 [FR Doc. E7-8355 Filed 5-1-07; 8:45 am] 

BILLING CODE 4140-01-P