[Federal Register Volume 72, Number 84 (Wednesday, May 2, 2007)]
[Notices]
[Pages 24322-24324]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-8355]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Public Teleconference Regarding Licensing and Collaborative 
Research Opportunities for: Use of CYP1B1*3 Genotyping To Predict 
Overall Survival in Patients With Prostate Cancer Prior to Treatment 
With Docetaxel; Dr. William D. Figg et al. (NCI)

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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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

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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

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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; 
[email protected].
    Collaborative Contact: John D. Hewes, Ph.D.; (301) 435-3121; 
[email protected].

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; [email protected]. 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